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Siteni S, Grichuk A, Shay JW. Telomerase in Cancer Therapeutics. Cold Spring Harb Perspect Biol 2024; 16:a041703. [PMID: 39349313 PMCID: PMC11610755 DOI: 10.1101/cshperspect.a041703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/02/2024]
Abstract
While silent in normal differentiated human tissues, telomerase is reactivated in most human cancers. Thus, telomerase is an almost universal oncology target. This update describes preclinical and clinical advancements using a variety of approaches to target telomerase. These include direct telomerase inhibitors, G-quadruplex DNA-interacting ligands, telomerase-based vaccine platforms, telomerase promoter-driven attenuated viruses, and telomerase-mediated telomere targeting approaches. While imetelstat has been recently approved by the Food and Drug Administration (FDA), several other approaches are in late-stage clinical development. The pros and cons of the major approaches will be reviewed.
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Affiliation(s)
- Silvia Siteni
- University of Texas Southwestern Medical Center, Department of Cell Biology, Dallas, Texas 75390, USA
| | - Anthony Grichuk
- University of Texas Southwestern Medical Center, Department of Cell Biology, Dallas, Texas 75390, USA
| | - Jerry W Shay
- University of Texas Southwestern Medical Center, Department of Cell Biology, Dallas, Texas 75390, USA
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2
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Truong P, Shen S, Joshi S, Islam MI, Zhong L, Raftery MJ, Afrasiabi A, Alinejad-Rokny H, Nguyen M, Zou X, Bhuyan GS, Sarowar CH, Ghodousi ES, Stonehouse O, Mohamed S, Toscan CE, Connerty P, Kakadia PM, Bohlander SK, Michie KA, Larsson J, Lock RB, Walkley CR, Thoms JAI, Jolly CJ, Pimanda JE. TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells. Nat Commun 2024; 15:7360. [PMID: 39198401 PMCID: PMC11358519 DOI: 10.1038/s41467-024-51646-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/metabolism
- Animals
- Drug Resistance, Neoplasm/genetics
- Drug Resistance, Neoplasm/drug effects
- Cell Line, Tumor
- Mice
- Myelodysplastic Syndromes/drug therapy
- Myelodysplastic Syndromes/genetics
- Myelodysplastic Syndromes/pathology
- Myelodysplastic Syndromes/metabolism
- CRISPR-Cas Systems
- Sumoylation/drug effects
- Ubiquitin-Protein Ligases/metabolism
- Ubiquitin-Protein Ligases/genetics
- DNA Damage/drug effects
- DNA Methylation/drug effects
- Xenograft Model Antitumor Assays
- DNA (Cytosine-5-)-Methyltransferase 1/metabolism
- DNA (Cytosine-5-)-Methyltransferase 1/genetics
- DNA (Cytosine-5-)-Methyltransferase 1/antagonists & inhibitors
- Female
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Affiliation(s)
- Peter Truong
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
| | - Sylvie Shen
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia
| | - Swapna Joshi
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia
| | | | - Ling Zhong
- Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW, Australia
| | - Mark J Raftery
- Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW, Australia
| | - Ali Afrasiabi
- UNSW BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia
| | - Hamid Alinejad-Rokny
- UNSW BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia
- Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Sydney, NSW, Australia
| | - Mary Nguyen
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia
| | - Xiaoheng Zou
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia
| | | | | | - Elaheh S Ghodousi
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
| | | | - Sara Mohamed
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
- UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia
| | - Cara E Toscan
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
- UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia
| | - Patrick Connerty
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
- UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia
| | - Purvi M Kakadia
- Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Stefan K Bohlander
- Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Katharine A Michie
- Structural Biology Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW, Australia
| | - Jonas Larsson
- Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Centre, Lund University, Lund, Sweden
| | - Richard B Lock
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
- UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia
| | - Carl R Walkley
- St Vincent's Institute of Medical Research, University of Melbourne, Melbourne, VIC, Australia
- Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
| | - Julie A I Thoms
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia
| | | | - John E Pimanda
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia.
- Haematology Department, Prince of Wales Hospital, Sydney, NSW, Australia.
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3
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Tang Y, Wang H, Zhang Z, Yao Y, Han Y, Wu D. DIAPH1 mutations predict a favorable outcome for de novo MDS. Cancer Lett 2024; 598:217125. [PMID: 39084456 DOI: 10.1016/j.canlet.2024.217125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 07/10/2024] [Accepted: 07/17/2024] [Indexed: 08/02/2024]
Abstract
DIAPH1, a member of the formins family and a Rho effector, was found to be involved in thrombocytopoiesis, and the process of MDS in mice with unknown pathogenesis. In this study, we reported a preliminary study about the heterogeneity in the clinical features and outcomes of DIAPH1 mutations in MDS. DIAPH1 frameshift mutations were identified in 20 out of 88 MDS patients, including 11 frameshift mutations locating at 140892588-141000567 (5q31.3), which causes structure changes at FH1 domain. DIAPH1 mutated cases were correlated with lower megakaryocyte dysplasia in lower-risk patients (IPSS-M score <0) at first diagnosis, and higher megakaryocyte counts pre-transplant. The megakaryopoiesis-related genes: GP1BA and SETBP1 mutation were positively and negatively associated with DIAPH1 mutation, respectively. DIAPH1 mutated cases showed superior overall survival of all patients and low-risk cohorts. In conclusion, we found DIAPH1 frameshift mutations are implicated in megakaryopoiesis of MDS and correlated with superior prognosis.
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Affiliation(s)
- Yaqiong Tang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Hong Wang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Ziyan Zhang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Yifang Yao
- Suzhou Hongci Hematology Hospital, Suzhou, China
| | - Yue Han
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China; State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China.
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China; State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China.
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4
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Liu S, Joshi K, Zhang L, Li W, Mack R, Runde A, Hagen PA, Barton K, Breslin P, Ji HL, Kini AR, Wang Z, Zhang J. Caspase 8 deletion causes infection/inflammation-induced bone marrow failure and MDS-like disease in mice. Cell Death Dis 2024; 15:278. [PMID: 38637559 PMCID: PMC11026525 DOI: 10.1038/s41419-024-06660-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 04/01/2024] [Accepted: 04/08/2024] [Indexed: 04/20/2024]
Abstract
Myelodysplastic syndromes (MDS) are a heterogeneous group of pre-leukemic hematopoietic disorders characterized by cytopenia in peripheral blood due to ineffective hematopoiesis and normo- or hypercellularity and morphologic dysplasia in bone marrow (BM). An inflammatory BM microenvironment and programmed cell death of hematopoietic stem/progenitor cells (HSPCs) are thought to be the major causes of ineffective hematopoiesis in MDS. Pyroptosis, apoptosis and necroptosis (collectively, PANoptosis) are observed in BM tissues of MDS patients, suggesting an important role of PANoptosis in MDS pathogenesis. Caspase 8 (Casp8) is a master regulator of PANoptosis, which is downregulated in HSPCs from most MDS patients and abnormally spliced in HSPCs from MDS patients with SRSF2 mutation. To study the role of PANoptosis in hematopoiesis, we generated inducible Casp8 knockout mice (Casp8-/-). Mx1-Cre-Casp8-/- mice died of BM failure within 10 days of polyI:C injections due to depletion of HSPCs. Rosa-ERT2Cre-Casp8-/- mice are healthy without significant changes in BM hematopoiesis within the first 1.5 months after Casp8 deletion. Such mice developed BM failure upon infection or low dose polyI:C/LPS injections due to the hypersensitivity of Casp8-/- HSPCs to infection or inflammation-induced necroptosis which can be prevented by Ripk3 deletion. However, impaired self-renewal capacity of Casp8-/- HSPCs cannot be rescued by Ripk3 deletion due to activation of Ripk1-Tbk1 signaling. Most importantly, mice transplanted with Casp8-/- BM cells developed MDS-like disease within 4 months of transplantation as demonstrated by anemia, thrombocytopenia and myelodysplasia. Our study suggests an essential role for a balance in Casp8, Ripk3-Mlkl and Ripk1-Tbk1 activities in the regulation of survival and self-renewal of HSPCs, the disruption of which induces inflammation and BM failure, resulting in MDS-like disease.
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Affiliation(s)
- Shanhui Liu
- Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
- Department of Cancer Biology, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
- Lanzhou University Second Hospital, Key Laboratory of Urological Diseases in Gansu Province, Lanzhou, Gansu, 730030, China
| | - Kanak Joshi
- Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
- Department of Cancer Biology, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
| | - Lei Zhang
- Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
- Department of Cancer Biology, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, National Clinical Research Center for Hematologic Diseases, Soochow University, Suzhou, 215123, China
| | - Wenyan Li
- Lanzhou University Second Hospital, Key Laboratory of Urological Diseases in Gansu Province, Lanzhou, Gansu, 730030, China
| | - Ryan Mack
- Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
- Department of Cancer Biology, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
| | - Austin Runde
- Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
- Department of Cancer Biology, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
| | - Patrick A Hagen
- Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
- Department of Medicine, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
| | - Kevin Barton
- Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
- Department of Medicine, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
| | - Peter Breslin
- Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
- Department of Cancer Biology, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
- Departments of Biology and Molecular/Cellular Physiology, Loyola University Chicago, Maywood, IL, 60153, USA
| | - Hong-Long Ji
- Department of Surgery, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
| | - Ameet R Kini
- Departments of Pathology and Radiation Oncology, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA
| | - Zhiping Wang
- Lanzhou University Second Hospital, Key Laboratory of Urological Diseases in Gansu Province, Lanzhou, Gansu, 730030, China.
| | - Jiwang Zhang
- Oncology Institute, Cardinal Bernardin Cancer Canter, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA.
- Department of Cancer Biology, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA.
- Departments of Pathology and Radiation Oncology, Loyola University Chicago Medical Center, Maywood, IL, 60153, USA.
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5
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Nakagawa N, Ishiyama K, Usuki K, Takada S, Tomikawa T, Handa H, Katsuoka Y, Hirano D, Sezaki N, Sumi M, Fujisawa S, Taniguchi Y, Mugitani A, Yoshimura T, Ohtsuka E, Takase K, Suehiro Y, Ota S, Kajiguchi T, Maeda T, Yamamoto M, Ohtake S, Katsumi A, Kiyoi H, Matsumura I, Miyazaki Y. Outcomes of transplant-eligible patients with myelodysplastic syndrome with excess blasts registered in an observational study: The JALSG-CS11-MDS-SCT. Ann Hematol 2024; 103:307-320. [PMID: 37940714 DOI: 10.1007/s00277-023-05527-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 10/26/2023] [Indexed: 11/10/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the sole curative therapy for myelodysplastic syndrome (MDS). However, whether bridging therapy (BRT) including azacitidine (AZA) and combination chemotherapy (CCT) prior to allo-SCT should be performed is unclear. We analyzed BRT and the outcomes of patients with myelodysplastic syndrome with excess blasts (MDS-EB) who were ≤ 70 years old at the time of registration for a prospective observational study to clarify the optimal allo-SCT strategy for high-risk MDS. A total of 371 patients were included in this study. Among 188 patients (50.7%) who were considered for allo-SCT, 141 underwent allo-SCT. Among the patients who underwent allo-SCT, 64 received AZA, 29 received CCT, and 26 underwent allo-SCT without BRT as the initial treatment. Multivariate analysis identified BRT as an independent factor influencing overall survival (AZA vs. without BRT, hazard ratio [HR] 3.33, P = 0.005; CCT vs. without BRT, HR 3.82, P = 0.003). In multivariate analysis, BRT was independently associated with progression-free survival (AZA vs. without BRT: HR, 2.23; P = 0.041; CCT vs. without BRT: HR, 2.94; P = 0.010). Transplant-eligible patients with MDS-EB should undergo allo-SCT when clinically acceptable, and upfront allo-SCT without BRT may be superior to AZA or CCT.
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Affiliation(s)
- Noriharu Nakagawa
- Department of Internal Medicine, Keiju Medical Center, Nanao, Japan
- Department of Hematology, Kanazawa University Hospital, Kanazawa, Japan
| | - Ken Ishiyama
- Department of Hematology, Kanazawa University Hospital, Kanazawa, Japan.
- Department of Hematology, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku, Tokyo, 162-8655, Japan.
| | - Kensuke Usuki
- Department of Hematology, NTT Medical Center Tokyo, Shinagawa, Japan
| | - Satoru Takada
- Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan
| | - Tatsuki Tomikawa
- Department of Hematology, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Hiroshi Handa
- Department of Hematology, Gunma University Hospital, Maebashi, Japan
| | - Yuna Katsuoka
- Department of Hematology, Sendai Medical Center, National Hospital Organization, Sendai, Japan
| | - Daiki Hirano
- Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Nobuo Sezaki
- Department of Hematology, Chugoku Central Hospital, Miyukichokamiiwanari, Japan
| | - Masahiko Sumi
- Department of Hematology, Nagano Red Cross Hospital, Nagano, Japan
| | - Shin Fujisawa
- Department of Hematology, Yokohama City University Medical Center, Yokohama, Japan
| | - Yasuhiro Taniguchi
- Department of Hematology and Rheumatology, Kindai University Hospital, Osakasayama, Japan
| | | | - Takuro Yoshimura
- Department of Hematology, Osaka City General Hospital, Osaka, Japan
| | - Eiichi Ohtsuka
- Department of Hematology, Oita Prefectural Hospital, Oita, Japan
| | - Ken Takase
- Department of Hematology, Kyushu Medical Center, Fukuoka, Japan
| | - Youko Suehiro
- Department of Hematology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Shuichi Ota
- Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan
| | - Tomohiro Kajiguchi
- Department of Hematology and Oncology, Tosei General Hospital, Seto, Japan
| | - Tomoya Maeda
- Department of Hemato-Oncology, Saitama International Medical Center, Saitama Medical University, Hidaka, Japan
| | - Masahide Yamamoto
- Department of Hematology, Tokyo Medical and Dental University, Bunkyo, Japan
| | - Shigeki Ohtake
- Department of Hematology, Kanazawa University Hospital, Kanazawa, Japan
| | - Akira Katsumi
- Department of Hematology, National Center for Geriatrics and Gerontology, Obu, Japan
| | - Hitoshi Kiyoi
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Itaru Matsumura
- Department of Hematology and Rheumatology, Kindai University Hospital, Osakasayama, Japan
| | - Yasushi Miyazaki
- Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan
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Hellström-Lindberg ES, Kröger N. Clinical decision-making and treatment of myelodysplastic syndromes. Blood 2023; 142:2268-2281. [PMID: 37874917 DOI: 10.1182/blood.2023020079] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 09/22/2023] [Accepted: 10/12/2023] [Indexed: 10/26/2023] Open
Abstract
ABSTRACT The myelodysplastic syndromes (MDSs) constitute a profoundly heterogeneous myeloid malignancy with a common origin in the hemopoietic stem cell compartment. Consequently, patient management and treatment are as heterogeneous. Decision-making includes identifying risk, symptoms, and options for an individual and conducting a risk-benefit analysis. The only potential cure is allogeneic stem cell transplantation, and albeit the fraction of patients with MDS who undergo transplant increase over time because of better management and increased donor availability, a majority are not eligible for this intervention. Current challenges encompass to decrease the relapse risk, the main cause of hematopoietic stem cell transplantation failure. Hypomethylating agents (HMAs) constitute firstline treatment for higher-risk MDSs. Combinations with other drugs as firstline treatment has, to date, not proven more efficacious than monotherapy, although combinations approved for acute myeloid leukemia, including venetoclax, are under evaluation and often used as rescue treatment. The treatment goal for lower-risk MDS is to improve cytopenia, mainly anemia, quality of life, and, possibly, overall survival. Erythropoiesis-stimulating agents (ESAs) constitute firstline treatment for anemia and have better and more durable responses if initiated before the onset of a permanent transfusion need. Treatment in case of ESA failure or ineligibility should be tailored to the main disease mechanism: immunosuppression for hypoplastic MDS without high-risk genetics, lenalidomide for low-risk del(5q) MDS, and luspatercept for MDS with ring sideroblasts. Approved therapeutic options are still scarcer for MDS than for most other hematologic malignancies. Better tools to match disease biology with treatment, that is, applied precision medicines are needed to improve patient outcome.
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Affiliation(s)
- Eva S Hellström-Lindberg
- Department of Medicine, Karolinska Institutet, Center for Hematology and Regenerative Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Nicolaus Kröger
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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7
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Rydén J, Clements M, Wikman A, Hellström-Lindberg E, Edgren G, Höglund P. Red blood cell alloimmunization in myelodysplastic syndromes: Associations with sex, DAT-positivity, and increased transfusion needs. Transfusion 2023; 63:2040-2051. [PMID: 37818926 DOI: 10.1111/trf.17562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 08/10/2023] [Accepted: 08/15/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND Many patients with myelodysplastic syndromes (MDS) need repeated red blood cell transfusions which entails a risk of immunization and antibody formation. Associations between alloantibodies, autoantibodies and increased transfusion requirements have been reported, but their relationship remains unclear. In this study, we analyzed factors potentially associated with red blood cell alloimmunization, as well as changes in transfusion intensity and post-transfusion hemoglobin increments. METHODS In a retrospective cohort study, we linked Swedish MDS patients diagnosed between 2003 and 2017 to transfusion and immunohematology data. Potentially associated factors were analyzed using Cox proportional hazards regression. The transfusion rate after detected alloimmunization was analyzed using a fixed effects Poisson regression. Post-transfusion hemoglobin increments before and after alloimmunization were compared using a mixed effects regression. RESULTS Alloantibodies following MDS diagnosis were detected in 50 out of 429 patients (11.7%). Female sex and a positive direct antiglobulin test (DAT) were independently associated with alloimmunization, with hazard ratios of 2.02 (95% confidence interval [CI] 1.08-3.78) and 9.72 (95% CI, 5.31-17.74), respectively. The transfusion rate following alloimmunization was increased with an incidence rate ratio of 1.33 (95% CI, 0.98-1.80) and the post-transfusion hemoglobin increment after alloimmunization was 1.40 g/L (95% CI, 0.52-2.28) lower per red blood cell unit (p = .002) compared to before alloimmunization, in multivariable analyses. DISCUSSION Alloimmunization against blood group antigens was associated with sex, DAT-positivity, increased transfusion needs, and lower post-transfusion hemoglobin increments. These findings warrant further investigation to evaluate the clinical significance of up-front typing and prophylactic antigen matching in patients with MDS.
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Affiliation(s)
- Jenny Rydén
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
| | - Mark Clements
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Agneta Wikman
- Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Eva Hellström-Lindberg
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
| | - Gustaf Edgren
- Department of Cardiology, Södersjukhuset, Stockholm, Sweden
- Department of Medicine, Solna, Division of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden
| | - Petter Höglund
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
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8
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Park SH, Kim HK, Jeong J, Lee SH, Lee YJ, Kim YJ, Jo JC, Lim JH. Research use only and cell population data items obtained from the Beckman Coulter DxH800 automated hematology analyzer are useful in discriminating MDS patients from those with cytopenia without MDS. J Hematop 2023; 16:143-154. [PMID: 38175401 DOI: 10.1007/s12308-023-00552-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 06/26/2023] [Indexed: 01/05/2024] Open
Abstract
We investigated the performance of research use only/cell population data (RUO/CPD) items obtained from the Beckman Coulter DxH800 automated hematologic analyzer in discriminating MDS patients from cytopenic patients without MDS.Total of 14 routine CBC, 18 research use only (RUO) items, and 70 CPD items were obtained retrospectively at diagnosis. The results were then compared between 94 MDS patients and 100 cytopenic patients without MDS. In items with statistically significant differences, receiver operating characteristic (ROC) analysis was performed and the results were compared.Four CBC/RUO items [red cell distribution width-standard deviation (RDW-SD), immature reticulocyte fraction (IRF), mean sphered cell volume (MSCV), high light scatter reticulocytes (HLR)], and two CPD items [mean volume of neutrophils (NE-V-Mean) and mean volume of early granulated cells (EGC-V-Mean)] showed area-under the curve (AUC) scores > 0.750. Notably, four RUO/CPD items (MSCV > 81.4/HLR > 0.15%/NE-V-Mean > 145/EGC-V-Mean > 156) showed high sensitivity (91.9%/93.6%/88.1%/90.2%, respectively) in discriminating MDS patients from cytopenic patients without MDS. With these six items, scores ≥ 4 (defined as ≥ 4 items exceeding cutoff values out of six items) showed AUC scores/sensitivity/specificity/accuracy (0.891/87.3%/79.0%/83.0%, respectively).Six CBC/RUO/CPD items showed satisfactory AUC scores of > 0.750, and four RUO/CPD items showed high sensitivity in discriminating MDS patients from cytopenic patients without MDS. Scoring system with six items showed high sensitivity, specificity, and accuracy with decision criteria of ≥ 4 scores. Therefore, DxH800 RUO/CPD items would be useful in discriminating MDS patients from cytopenic patients without MDS.
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Affiliation(s)
- Sang Hyuk Park
- Department of Laboratory Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
| | - Hyun-Ki Kim
- Department of Laboratory Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
| | - Joseph Jeong
- Department of Laboratory Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
| | - Seon-Ho Lee
- Department of Laboratory Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
| | - Yoo Jin Lee
- Department of Hematology and Cellular Therapy, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
| | - Yoo Jin Kim
- Department of Hematology and Cellular Therapy, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
| | - Jae-Cheol Jo
- Department of Hematology and Cellular Therapy, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
| | - Ji-Hun Lim
- Department of Laboratory Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea.
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9
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Ejam SS, Saleh RO, Catalan Opulencia MJ, Najm MA, Makhmudova A, Jalil AT, Abdelbasset WK, Al-Gazally ME, Hammid AT, Mustafa YF, Sergeevna SE, Karampoor S, Mirzaei R. Pathogenic role of 25-hydroxycholesterol in cancer development and progression. Future Oncol 2022; 18:4415-4442. [PMID: 36651359 DOI: 10.2217/fon-2022-0819] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 12/06/2022] [Indexed: 01/19/2023] Open
Abstract
Cholesterol is an essential lipid that serves several important functions, including maintaining the homeostasis of cells, acting as a precursor to bile acid and steroid hormones and preserving the stability of membrane lipid rafts. 25-hydroxycholesterol (25-HC) is a cholesterol derivative that may be formed from cholesterol. 25-HC is a crucial component in various biological activities, including cholesterol metabolism. In recent years, growing evidence has shown that 25-HC performs a critical function in the etiology of cancer, infectious diseases and autoimmune disorders. This review will summarize the latest findings regarding 25-HC, including its biogenesis, immunomodulatory properties and role in innate/adaptive immunity, inflammation and the development of various types of cancer.
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Affiliation(s)
| | - Raed Obaid Saleh
- Department of Pharmacy, Al-Maarif University College, Al-Anbar, Iraq
| | | | - Mazin Aa Najm
- Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Aziza Makhmudova
- Department of Social Sciences & Humanities, Samarkand State Medical Institute, Samarkand, Uzbekistan
- Department of Scientific Affairs, Tashkent State Dental Institute, Makhtumkuli Street 103, Tashkent, 100047, Uzbekistan
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq
| | - Walid Kamal Abdelbasset
- Department of Health & Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | | | - Ali Thaeer Hammid
- Computer Engineering Techniques Department, Faculty of Information Technology, Imam Ja'afar Al-Sadiq University, Baghdad, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Sergushina Elena Sergeevna
- National Research Ogarev Mordovia State University, 68 Bolshevitskaya Street, Republic of Mordovia, Saransk, 430005, Russia
| | - Sajad Karampoor
- Gastrointestinal & Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Venom & Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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10
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Santini V, Giagounidis A, Pelligra CG, Franco-Villalobos C, Tang D, Morison J, Beach CL, Hu A, Platzbecker U, Fenaux P. Impact of Lenalidomide Treatment on Overall Survival in Patients With Lower-Risk, Transfusion-Dependent Myelodysplastic Syndromes. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2022; 22:e874-e883. [PMID: 35710702 DOI: 10.1016/j.clml.2022.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 05/13/2022] [Accepted: 05/16/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND For patients with lower-risk (LR) myelodysplastic syndromes (MDS), overall survival (OS) is rarely a primary clinical trial endpoint. Treatments such as lenalidomide can reduce red blood cell (RBC) transfusion burden (TB) and serum ferritin, but the long-term impact on OS remains undetermined. PATIENTS AND METHODS Data from 3 trials evaluating lenalidomide in patients with LR-MDS (the phase 2 MDS-003 and phase 3 MDS-004 trials in del[5q]; the phase 3 trial MDS-005 in non-del[5q] patients) were pooled. Predictors of OS were assessed by multivariate analysis using time-dependent models for TB and RBC transfusion independence (RBC-TI), and a landmark analysis of RBC-TI at 17 weeks. Separate analyses using MDS-004 and MDS-005 data determined the relationship between OS and serum ferritin. RESULTS Median follow-up for MDS-003, MDS-004, and MDS-005 was 3.2, 3.0, and 1.7 years, respectively. In multivariate analyses, transfusion of ≥6 RBC units over 8 weeks was a significant predictor of shorter OS vs. 0 units in the time-dependent TB model (hazard ratio [HR] 4.65; 95% confidence interval [CI] 3.32-6.52; P < .0001). RBC-TI achievement was associated with prolonged OS in the time-dependent (HR 0.48; 95% CI 0.37-0.62; P < .0001) and landmark model (HR 0.57; 95% CI 0.44-0.75; P < .0001). Increased serum ferritin was associated with shorter OS (P < .0001). CONCLUSION This analysis of prospective trial data in patients with LR-MDS confirms lenalidomide may improve OS by reducing TB and serum ferritin. OS should be considered as an endpoint in future lower risk MDS clinical trials.
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Affiliation(s)
- Valeria Santini
- MDS Unit, AOU Careggi, DMSC, University of Florence. Florence, Italy.
| | - Aristoteles Giagounidis
- Department of Oncology, Haematology, and Palliative Care, Marien Hospital, Düsseldorf, Germany
| | | | | | - Derek Tang
- Formerly Bristol Myers Squibb, Princeton, NJ, USA
| | | | - C L Beach
- Formerly Bristol Myers Squibb, Princeton, NJ, USA
| | - Angela Hu
- Formerly Bristol Myers Squibb, Princeton, NJ, USA
| | - Uwe Platzbecker
- Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, Leipzig University Hospital, Leipzig, Germany
| | - Pierre Fenaux
- Service d'Hématologie Séniors, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Université de Paris, France
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11
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Khanam R, Shahzad M, Chaudhary SG, Ali F, Shah Z, Pachika PS, Ahmed Z, Chattaraj A, Masood A, Ahmed N, Bansal R, Balusu R, Shune L, Anwar F, Hematti P, McGuirk JP, Yacoub A, Mushtaq MU. Outcomes after venetoclax with hypomethylating agents in myelodysplastic syndromes: a systematic review and meta-analysis. Leuk Lymphoma 2022; 63:2671-2678. [DOI: 10.1080/10428194.2022.2084730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Razwana Khanam
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Moazzam Shahzad
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Sibgha Gull Chaudhary
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Fatima Ali
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Zunairah Shah
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Pranali S. Pachika
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Zahoor Ahmed
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Asmi Chattaraj
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Adeel Masood
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Nausheen Ahmed
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Rajat Bansal
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Ramesh Balusu
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Leyla Shune
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Faiz Anwar
- Division of Hematology/Oncology, Cleveland Clinic, Cleveland, OH, USA
| | - Peiman Hematti
- Division of Hematology/Oncology, University of Wisconsin School of Medicine & Public Health, Madison, WI, USA
| | - Joseph P. McGuirk
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Abdulraheem Yacoub
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Muhammad Umair Mushtaq
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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12
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Liu YC, Kwon J, Fabiani E, Xiao Z, Liu YV, Follo MY, Liu J, Huang H, Gao C, Liu J, Falconi G, Valentini L, Gurnari C, Finelli C, Cocco L, Liu JH, Jones AI, Yang J, Yang H, Thoms JAI, Unnikrishnan A, Pimanda JE, Pan R, Bassal MA, Voso MT, Tenen DG, Chai L. Demethylation and Up-Regulation of an Oncogene after Hypomethylating Therapy. N Engl J Med 2022; 386:1998-2010. [PMID: 35613022 PMCID: PMC9514878 DOI: 10.1056/nejmoa2119771] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Although hypomethylating agents are currently used to treat patients with cancer, whether they can also reactivate and up-regulate oncogenes is not well elucidated. METHODS We examined the effect of hypomethylating agents on SALL4, a known oncogene that plays an important role in myelodysplastic syndrome and other cancers. Paired bone marrow samples that were obtained from two cohorts of patients with myelodysplastic syndrome before and after treatment with a hypomethylating agent were used to explore the relationships among changes in SALL4 expression, treatment response, and clinical outcome. Leukemic cell lines with low or undetectable SALL4 expression were used to study the relationship between SALL4 methylation and expression. A locus-specific demethylation technology, CRISPR-DNMT1-interacting RNA (CRISPR-DiR), was used to identify the CpG island that is critical for SALL4 expression. RESULTS SALL4 up-regulation after treatment with hypomethylating agents was observed in 10 of 25 patients (40%) in cohort 1 and in 13 of 43 patients (30%) in cohort 2 and was associated with a worse outcome. Using CRISPR-DiR, we discovered that demethylation of a CpG island within the 5' untranslated region was critical for SALL4 expression. In cell lines and patients, we confirmed that treatment with a hypomethylating agent led to demethylation of the same CpG region and up-regulation of SALL4 expression. CONCLUSIONS By combining analysis of patient samples with CRISPR-DiR technology, we found that demethylation and up-regulation of an oncogene after treatment with a hypomethylating agent can indeed occur and should be further studied. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).
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Affiliation(s)
- Yao-Chung Liu
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Junsu Kwon
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Emiliano Fabiani
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Zhijian Xiao
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Yanjing V Liu
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Matilde Y Follo
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Jinqin Liu
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Huijun Huang
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Chong Gao
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Jun Liu
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Giulia Falconi
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Lia Valentini
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Carmelo Gurnari
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Carlo Finelli
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Lucio Cocco
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Jin-Hwang Liu
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Adrianna I Jones
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Junyu Yang
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Henry Yang
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Julie A I Thoms
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Ashwin Unnikrishnan
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - John E Pimanda
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Rongqing Pan
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Mahmoud A Bassal
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Maria T Voso
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Daniel G Tenen
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
| | - Li Chai
- From the Department of Pathology, Brigham and Women's Hospital (Y.-C.L., C. Gao, Jun Liu, J.Y., L. Chai), Harvard Stem Cell Institute, Harvard Medical School (A.I.J., M.A.B., D.G.T.), and the Department of Medical Oncology, Dana-Farber Cancer Institute (R.P.) - all in Boston; the Division of Hematology, Department of Medicine, Taipei Veterans General Hospital (Y.-C.L.), and the Faculty of Medicine and the Program in Molecular Medicine, Institute of Biopharmaceutical Sciences, School of Life Science, National Yang Ming Chiao Tung University (Y.-C.L., J.-H.L.) - both in Taipei, Taiwan; the Cancer Science Institute of Singapore, Singapore (J.K., Y.V.L., H.Y., M.A.B., D.G.T.); the Department of Biomedicine and Prevention, University of Rome Tor Vergata (E.F., G.F., L.V., C. Gurnari, M.T.V.), and UniCamillus-Saint Camillus International University of Health Sciences (E.F.), Rome, and Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna (M.Y.F., L. Cocco), and IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" (C.F.), Bologna - all in Italy; the National Clinical Research Center for Blood Diseases and State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (Z.X., Jinqin Liu, H.H.); and the School of Medical Sciences and Lowy Cancer Research Centre (J.A.I.T., J.E.P.) and Prince of Wales Clinical School and Lowy Cancer Research Centre (A.U., J.E.P.), Faculty of Medicine, University of New South Wales, Sydney, and the Department of Hematology, Prince of Wales Hospital, Randwick, NSW (J.E.P.) - both in Australia
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Incidence of myelodysplastic syndromes in Finland 1997-2016. Leuk Res 2022; 116:106839. [DOI: 10.1016/j.leukres.2022.106839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 03/24/2022] [Accepted: 03/31/2022] [Indexed: 11/22/2022]
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Smetana K, Klamová H, Mikulenková D, Čermák J, Otevřelová P, Karban J, Trněný M. The cell body space occupied by the nucleus during the cell differentiation in human lymphocytic, granulocytic and erythroid cell lineages. Physiol Res 2021; 70:701-707. [PMID: 34505521 DOI: 10.33549/physiolres.934691] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
The present nuclear and cell body diameter measurements demonstrated size differences of the approximate cell space estimate occupied by the cell nucleus during the cell differentiation in lymphocytic, granulocytic and erythroid cell lineages. These lineages were used as convenient models because all differentiation steps were easily identified and accessible in diagnostic peripheral blood or bone marrow smears of blood donors (BDs), patients suffering from chronic lymphocytic leukemia (CLL), patients with chronic myeloid leukemia (CML) and refractory anemia (RA) of the myelodysplastic syndrome (MDS). The cell space occupied by the nucleus was constant and did not change during the cell differentiation in the lymphocytic cell lineages of BDs and CLL patients despite the decreased cell size. In contrary, the cell space occupied by the nucleus markedly decreased in differentiating cells of granulocytic and erythroid lineages of patients suffering from CML. In the erythroid cell lineage in patients with RA of MDS the small reduction of the cell space occupied by the nucleus during the differentiation was not significant. The measurements also indicated that in progenitor cells of all studied cell lineages nuclei occupied more than 70 % of the cell space. Thus, the nucleus-cytoplasmic morphological and functional equilibrium appeared to be characteristic for each differentiation step and each specific cell lineage.
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Affiliation(s)
- K Smetana
- Institute of Hematology and Blood Transfusion, Prague 2, Czech Republic.
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Zou J, Shi Q, Chen H, Juskevicius R, Zinkel SS. Programmed necroptosis is upregulated in low-grade myelodysplastic syndromes and may play a role in the pathogenesis. Exp Hematol 2021; 103:60-72.e5. [PMID: 34563605 PMCID: PMC9069723 DOI: 10.1016/j.exphem.2021.09.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/16/2021] [Accepted: 09/17/2021] [Indexed: 11/17/2022]
Abstract
Myelodysplastic syndrome (MDS) is characterized by persistent cytopenias and evidence of morphologic dysplasia in the bone marrow (BM). Excessive hematopoietic programmed cell death (PCD) and inflammation have been observed in the bone marrow of patients with MDS, and are thought to play a significant role in the pathogenesis of the disease. Necroptosis is a major pathway of PCD that incites inflammation; however, the role of necroptosis in human MDS has not been extensively investigated. To assess PCD status in newly diagnosed MDS, we performed immunofluorescence staining with computational image analysis of formalin-fixed, paraffin-embedded BM core biopsies using cleaved caspase-3 (apoptosis marker) and necroptosis markers (receptor-interacting serine/threonine-protein kinase 1 [RIPK1], phospho-mixed lineage kinase domain-like protein [pMLKL]). Patients with MDS, but not controls without MDS or patients with de novo acute myeloid leukemia, had significantly increased expression of RIPK1 and pMLKL but not cleaved caspase-3, which was most evident in morphologically low-grade MDS (<5% BM blasts) and in MDS with low International Prognostic Scoring System risk score. RIPK1 expression highly correlated with the distribution of CD71+ erythroid precursors but not with CD34+ blast cells. We found that necroptosis is upregulated in early/low-grade MDS relative to control participants, warranting further study to define the role of necroptosis in the pathogenesis of MDS and as a potential biomarker for the diagnosis of low-grade MDS.
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Affiliation(s)
- Jing Zou
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Qiong Shi
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Heidi Chen
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Ridas Juskevicius
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Sandra S Zinkel
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN.
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Shahid Z, Hassan S, Ghazanfar S, Kaneez M, Khan MS, Tariq HT, Jawad A, Shuaib A, Bhatti AA, Razzaq MT. Investigating the Role of Ferritin in Determining Sexual Underdevelopment in Beta-Thalassemia Major Patients: A Cross-Sectional Analysis From Pakistan. Cureus 2021; 13:e15572. [PMID: 34277194 PMCID: PMC8270070 DOI: 10.7759/cureus.15572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2021] [Indexed: 12/03/2022] Open
Abstract
Background Beta-thalassemia major, a genetic disorder, delineates a vast spectrum of hematological and endocrinological complications. Elevated serum ferritin levels in beta-thalassemia patients represent various transfusion-related complications including infection, hemochromatosis, and severe iron overload that might lead to endocrinopathies such as hypogonadism leading to sexual underdevelopment. Our study, thus, aims to explore the role of ferritin in determining sexual underdevelopment in such patients. Methods This multicentric cross-sectional study included a total of 120 beta-thalassemia patients. The sexual development of the patients was assessed using the Tanner staging system. Serum ferritin levels and other demographical parameters of the patients were collected. Independent-samples t-test, chi-square test, and receiver operating characteristic (ROC) curve were used to analyze the data. Results Out of 120 patients, 70 patients were males with a mean age of 18.95 ± 4.21 years. According to the Tanner staging system, 48 patients were sexually underdeveloped while 72 patients achieved sexual maturity. ROC curve analysis showed that ferritin levels at a cutoff value of 4900 mg/dL were 73.7% sensitive and 71.1% specific to predict sexual underdevelopment in beta-thalassemia patients. Conclusions Elevated serum ferritin levels were moderately sensitive and specific in predicting sexual underdevelopment in beta-thalassemia patients. This can serve as a low-cost parameter in determining sexual underdevelopment in such patients. More prospective cohort studies are needed to establish the association between elevated serum ferritin levels and sexual underdevelopment.
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Affiliation(s)
- Zia Shahid
- Internal Medicine, Rawalpindi Medical University, Rawalpindi, PAK
| | - Sarmad Hassan
- Internal Medicine, Rawalpindi Medical University, Rawalpindi, PAK
| | | | - Mehwish Kaneez
- Internal Medicine, Rawalpindi Medical University, Rawalpindi, PAK
| | | | | | - Arslan Jawad
- Internal Medicine, Hamad Medical Corporation, Doha, QAT
| | - Atifa Shuaib
- Pathology, Rawalpindi Medical University, Rawalpindi, PAK
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17
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Radhachandran A, Garikipati A, Iqbal Z, Siefkas A, Barnes G, Hoffman J, Mao Q, Das R. A machine learning approach to predicting risk of myelodysplastic syndrome. Leuk Res 2021; 109:106639. [PMID: 34171604 DOI: 10.1016/j.leukres.2021.106639] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/18/2021] [Accepted: 06/05/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Early myelodysplastic syndrome (MDS) diagnosis can allow physicians to provide early treatment, which may delay advancement of MDS and improve quality of life. However, MDS often goes unrecognized and is difficult to distinguish from other disorders. We developed a machine learning algorithm for the prediction of MDS one year prior to clinical diagnosis of the disease. METHODS Retrospective analysis was performed on 790,470 patients over the age of 45 seen in the United States between 2007 and 2020. A gradient boosted decision tree model (XGB) was built to predict MDS diagnosis using vital signs, lab results, and demographics from the prior two years of patient data. The XGB model was compared to logistic regression (LR) and artificial neural network (ANN) models. The models did not use blast percentage and cytogenetics information as inputs. Predictions were made one year prior to MDS diagnosis as determined by International Classification of Diseases (ICD) codes, 9th and 10th revisions. Performance was assessed with regard to area under the receiver operating characteristic curve (AUROC). RESULTS On a hold-out test set, the XGB model achieved an AUROC value of 0.87 for prediction of MDS one year prior to diagnosis, with a sensitivity of 0.79 and specificity of 0.80. The XGB model was compared against LR and ANN models, which achieved an AUROC of 0.838 and 0.832, respectively. CONCLUSIONS Machine learning may allow for early MDS diagnosis MDS and more appropriate treatment administration.
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18
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Acevedo A, Merino A, Boldú L, Molina Á, Alférez S, Rodellar J. A new convolutional neural network predictive model for the automatic recognition of hypogranulated neutrophils in myelodysplastic syndromes. Comput Biol Med 2021; 134:104479. [PMID: 34010795 DOI: 10.1016/j.compbiomed.2021.104479] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 04/22/2021] [Accepted: 05/06/2021] [Indexed: 01/02/2023]
Abstract
BACKGROUND Dysplastic neutrophils commonly show at least 2/3 reduction of the content of cytoplasmic granules by morphologic examination. Recognition of less granulated dysplastic neutrophils by human eyes is difficult and prone to inter-observer variability. To tackle this problem, we proposed a new deep learning model (DysplasiaNet) able to automatically recognize the presence of hypogranulated dysplastic neutrophils in peripheral blood. METHODS Eight models were generated by varying convolutional blocks, number of layer nodes and fully connected layers. Each model was trained for 20 epochs. The five most accurate models were selected for a second stage, being trained again from scratch for 100 epochs. After training, cut-off values were calculated for a granularity score that discerns between normal and dysplastic neutrophils. Furthermore, a threshold value was obtained to quantify the minimum proportion of dysplastic neutrophils in the smear to consider that the patient might have a myelodysplastic syndrome (MDS). The final selected model was the one with the highest accuracy (95.5%). RESULTS We performed a final proof of concept with new patients not involved in previous steps. We reported 95.5% sensitivity, 94.3% specificity, 94% precision, and a global accuracy of 94.85%. CONCLUSIONS The primary contribution of this work is a predictive model for the automatic recognition in an objective way of hypogranulated neutrophils in peripheral blood smears. We envision the utility of the model implemented as an evaluation tool for MDS diagnosis integrated in the clinical laboratory workflow.
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Affiliation(s)
- Andrea Acevedo
- Haematology and Cytology Unit, Core Laboratory, Biochemical and Molecular Genetics Department, CDB. Hospital Clínic of Barcelona-IDIBAPS, Barcelona, Spain; Department of Mathematics, Technical University of Catalonia, Barcelona East Engineering School, Barcelona, Spain
| | - Anna Merino
- Haematology and Cytology Unit, Core Laboratory, Biochemical and Molecular Genetics Department, CDB. Hospital Clínic of Barcelona-IDIBAPS, Barcelona, Spain.
| | - Laura Boldú
- Haematology and Cytology Unit, Core Laboratory, Biochemical and Molecular Genetics Department, CDB. Hospital Clínic of Barcelona-IDIBAPS, Barcelona, Spain
| | - Ángel Molina
- Haematology and Cytology Unit, Core Laboratory, Biochemical and Molecular Genetics Department, CDB. Hospital Clínic of Barcelona-IDIBAPS, Barcelona, Spain
| | - Santiago Alférez
- Department of Applied Mathematics and Computer Science, Universidad del Rosario, Bogotá, Colombia
| | - José Rodellar
- Department of Mathematics, Technical University of Catalonia, Barcelona East Engineering School, Barcelona, Spain
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Fan T, Feng X, Yokota A, Liu W, Tang Y, Yan X, Xiao H, Wang Y, Deng Z, Zhao P, Wang M, Wang H, Ma R, Hu X, Huang G. Arsenic Dispensing Powder Promotes Erythropoiesis in Myelodysplastic Syndromes via Downregulation of HIF1A and Upregulation of GATA Factors. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2021; 49:461-485. [PMID: 33641653 DOI: 10.1142/s0192415x2150021x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Traditional Chinese Medicine (TCM) is a practical medicine based on thousands of years of medical practice in China. Arsenic dispensing powder (ADP) has been used as a treatment for MDS patients with a superior efficacy on anemia at Xiyuan Hospital of China Academy of Chinese Medical Sciences. In this study, we retrospectively analyzed MDS patients that received ADP treatment in the past 9 years and confirmed that ADP improves patients' anemia and prolongs overall survival in intermediate-risk MDS patients. Then, we used the MDS transgenic mice model and cell line to explore the drug mechanism. In normal and MDS cells, ADP does not show cellular toxicity but promotes differentiation. In mouse MDS models, we observed that ADP showed significant efficacy on promoting erythropoiesis. In the BFU-E and CFU-E assays, ADP could promote erythropoiesis not only in normal clones but also in MDS clones. Mechanistically, we found that ADP could downregulate HIF1A in MDS clones through upregulation of VHL, P53 and MDM2, which is involved in two parallel pathways to downregulate HIF1A. We also confirmed that ADP upregulates GATA factors in normal clones. Thus, our clinical and experimental studies indicate that ADP is a promising drug to promote erythropoiesis in both MDS and normal clones with a superior outcome than current regular therapies. ADP promotes erythropoiesis in myelodysplastic syndromes via downregulation of HIF1A and upregulation of GATA factors.
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Affiliation(s)
- Teng Fan
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, P. R. China.,Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Xiaomin Feng
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Asumi Yokota
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Weiyi Liu
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, P. R. China
| | - Yuting Tang
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Xiaomei Yan
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Haiyan Xiao
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, P. R. China
| | - Yue Wang
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, P. R. China
| | - Zhongyang Deng
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, P. R. China
| | - Pan Zhao
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, P. R. China
| | - Mingjing Wang
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, P. R. China
| | - Hongzhi Wang
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, P. R. China
| | - Rou Ma
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, P. R. China
| | - Xiaomei Hu
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, P. R. China
| | - Gang Huang
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
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Rodríguez-García A, García-Vicente R, Morales ML, Ortiz-Ruiz A, Martínez-López J, Linares M. Protein Carbonylation and Lipid Peroxidation in Hematological Malignancies. Antioxidants (Basel) 2020; 9:E1212. [PMID: 33271863 PMCID: PMC7761105 DOI: 10.3390/antiox9121212] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/20/2020] [Accepted: 11/28/2020] [Indexed: 02/07/2023] Open
Abstract
Among the different mechanisms involved in oxidative stress, protein carbonylation and lipid peroxidation are both important modifications associated with the pathogenesis of several diseases, including cancer. Hematopoietic cells are particularly vulnerable to oxidative damage, as the excessive production of reactive oxygen species and associated lipid peroxidation suppress self-renewal and induce DNA damage and genomic instability, which can trigger malignancy. A richer understanding of the clinical effects of oxidative stress might improve the prognosis of these diseases and inform therapeutic strategies. The most common protein carbonylation and lipid peroxidation compounds, including hydroxynonenal, malondialdehyde, and advanced oxidation protein products, have been investigated for their potential effect on hematopoietic cells in several studies. In this review, we focus on the most important protein carbonylation and lipid peroxidation biomarkers in hematological malignancies, their role in disease development, and potential treatment implications.
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Affiliation(s)
- Alba Rodríguez-García
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041 Madrid, Spain; (A.R.-G.); (R.G.-V.); (M.L.M.); (A.O.-R.); (J.M.-L.)
| | - Roberto García-Vicente
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041 Madrid, Spain; (A.R.-G.); (R.G.-V.); (M.L.M.); (A.O.-R.); (J.M.-L.)
| | - María Luz Morales
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041 Madrid, Spain; (A.R.-G.); (R.G.-V.); (M.L.M.); (A.O.-R.); (J.M.-L.)
| | - Alejandra Ortiz-Ruiz
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041 Madrid, Spain; (A.R.-G.); (R.G.-V.); (M.L.M.); (A.O.-R.); (J.M.-L.)
| | - Joaquín Martínez-López
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041 Madrid, Spain; (A.R.-G.); (R.G.-V.); (M.L.M.); (A.O.-R.); (J.M.-L.)
- Department of Medicine, Medicine School, Universidad Complutense de Madrid, ES 28040 Madrid, Spain
| | - María Linares
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041 Madrid, Spain; (A.R.-G.); (R.G.-V.); (M.L.M.); (A.O.-R.); (J.M.-L.)
- Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, ES 28040 Madrid, Spain
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21
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De Witte T, Malcovati L, Fenaux P, Bowen D, Symeonidis A, Mittelman M, Stauder R, Sanz G, Čermák J, Langemeijer S, Hellström-Lindberg E, Germing U, Skov Holm M, Mądry K, Tatic A, Medina Almeida A, Savic A, Mandac Rogulj I, Itzykson R, Hoeks M, Gravdahl Garelius H, Culligan D, Kotsianidis I, Ades L, Van de Loosdrecht AA, Van Marrewijk C, Yu G, Crouch S, Smith A. Novel dynamic outcome indicators and clinical endpoints in myelodysplastic syndrome; the European LeukemiaNet MDS Registry and MDS-RIGHT project perspective. Haematologica 2020; 105:2516-2523. [PMID: 33054132 PMCID: PMC7604570 DOI: 10.3324/haematol.2020.266817] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Affiliation(s)
- Theo De Witte
- Department of Tumor Immunology - Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen; TdW and LM both contributed equally as co-first authors.
| | - Luca Malcovati
- Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia; TdW and LM both contributed equally as co-first authors.
| | - Pierre Fenaux
- Service d'Hématologie, Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris (AP-HP) and Université Paris 7, Paris.
| | - David Bowen
- St. James's Institute of Oncology, Leeds Teaching Hospitals, Leeds.
| | - Argiris Symeonidis
- Department of Medicine, Division of Hematology, University of Patras Medical School, Patras.
| | - Moshe Mittelman
- Department of Medicine A, Tel Aviv Sourasky (Ichilov) Medical Center and Sackler Medical Faculty, Tel Aviv University, Tel Aviv.
| | - Reinhard Stauder
- Department of Internal Medicine V (Haematology and Oncology), Innsbruck Medical University, Innsbruck.
| | - Guillermo Sanz
- Department of Haematology, Hospital Universitario y Politécnico La Fe, Valencia, and CIBERONC, Madrid.
| | - Jaroslav Čermák
- Department of Clinical Hematology, Inst. of Hematology and Blood Transfusion, Praha.
| | | | | | - Ulrich Germing
- Department of Haematology, Oncology and Clinical Immunology, Universitätsklinik Düsseldorf, Düsseldorf.
| | - Mette Skov Holm
- Department of Haematology, Aarhus University Hospital, Aarhus.
| | - Krzysztof Mądry
- Department of Haematology, Oncology and Internal Medicine, Warszawa Medical University, Warszawa.
| | - Aurelia Tatic
- Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest.
| | | | - Aleksandar Savic
- Clinic of Hematology - Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad.
| | - Inga Mandac Rogulj
- Department of Internal Medicine, Division of Hematology, Merkur University Hospital, Zagreb.
| | - Raphael Itzykson
- Service d'Hématologie, Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris (AP-HP) and Université Paris 7, Paris.
| | - Marlijn Hoeks
- Department of Hematology, Radboud University Medical Center, Nijmegen.
| | | | | | - Ioannis Kotsianidis
- Department of Hematology, Democritus University of Thrace Medical School, University Hospital of Alexandroupolis, Alexandroupolis.
| | - Lionel Ades
- Service d'Hématologie, Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris (AP-HP) and Université Paris 7, Paris.
| | - Arjan A Van de Loosdrecht
- Department of Hematology - Cancer Center Amsterdam, Amsterdam UMC, Location VU University Medical Center, Amsterdam.
| | | | - Ge Yu
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York.
| | - Simon Crouch
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York.
| | - Alex Smith
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York.
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22
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Affiliation(s)
- Mario Cazzola
- From Fondazione IRCCS Policlinico San Matteo and the University of Pavia, Pavia, Italy
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23
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Sibon D, Coman T, Rossignol J, Lamarque M, Kosmider O, Bayard E, Fouquet G, Rignault R, Topçu S, Bonneau P, Bernex F, Dussiot M, Deroy K, Laurent L, Callebert J, Launay JM, Georgin-Lavialle S, Courtois G, Maroteaux L, Vaillancourt C, Fontenay M, Hermine O, Côté F. Enhanced Renewal of Erythroid Progenitors in Myelodysplastic Anemia by Peripheral Serotonin. Cell Rep 2020; 26:3246-3256.e4. [PMID: 30893598 DOI: 10.1016/j.celrep.2019.02.071] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 12/30/2018] [Accepted: 02/20/2019] [Indexed: 10/27/2022] Open
Abstract
Tryptophan as the precursor of several active compounds, including kynurenine and serotonin, is critical for numerous important metabolic functions. Enhanced tryptophan metabolism toward the kynurenine pathway has been associated with myelodysplastic syndromes (MDSs), which are preleukemic clonal diseases characterized by dysplastic bone marrow and cytopenias. Here, we reveal a fundamental role for tryptophan metabolized along the serotonin pathway in normal erythropoiesis and in the physiopathology of MDS-related anemia. We identify, both in human and murine erythroid progenitors, a functional cell-autonomous serotonergic network with pro-survival and proliferative functions. In vivo studies demonstrate that pharmacological increase of serotonin levels using fluoxetine, a common antidepressant, has the potential to become an important therapeutic strategy in low-risk MDS anemia refractory to erythropoietin.
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Affiliation(s)
- David Sibon
- Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France
| | - Tereza Coman
- Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France; Département d'Hématologie, Gustave Roussy Cancer Campus Grand Paris, 94800 Villejuif, France
| | - Julien Rossignol
- Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France; Département d'Hématologie, Gustave Roussy Cancer Campus Grand Paris, 94800 Villejuif, France
| | - Mathilde Lamarque
- Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France
| | - Olivier Kosmider
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Paris, APHP, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre-Cochin, Paris 75014, France
| | - Elisa Bayard
- Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France
| | - Guillemette Fouquet
- Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France
| | - Rachel Rignault
- Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France
| | - Selin Topçu
- Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France
| | - Pierre Bonneau
- Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France
| | - Florence Bernex
- Institut de Recherche en Cancérologie de Montpellier, Montpellier 34298, France; INSERM, U1194, Network of Experimental Histology, BioCampus, CNRS, UMS3426, Montpellier 34094, France
| | - Michael Dussiot
- Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France
| | - Kathy Deroy
- INRS-Institut Armand-Frappier and Center for Interdisciplinary Research on Well-Being, Health, Society and Environment, Montreal, QC H7V 1B7, Canada
| | - Laetitia Laurent
- INRS-Institut Armand-Frappier and Center for Interdisciplinary Research on Well-Being, Health, Society and Environment, Montreal, QC H7V 1B7, Canada
| | - Jacques Callebert
- Service de Biochimie, INSERM U942, Hôpital Lariboisière, 75010 Paris, France
| | - Jean-Marie Launay
- Service de Biochimie, INSERM U942, Hôpital Lariboisière, 75010 Paris, France
| | - Sophie Georgin-Lavialle
- Département de Médecine Interne, Hôpital Tenon, Université Pierre et Marie Curie, AP-HP, 4 rue de la Chine, 75020 Paris, France
| | - Geneviève Courtois
- Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France
| | - Luc Maroteaux
- INSERM UMR-S1270, Sorbonne Universités, Université Pierre et Marie Curie, Institut du Fer à Moulin, 75005 Paris, France
| | - Cathy Vaillancourt
- INRS-Institut Armand-Frappier and Center for Interdisciplinary Research on Well-Being, Health, Society and Environment, Montreal, QC H7V 1B7, Canada
| | - Michaela Fontenay
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Paris, APHP, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre-Cochin, Paris 75014, France
| | - Olivier Hermine
- Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France; Department of Hematology, Hôpital Necker AP-HP, 75015 Paris, France
| | - Francine Côté
- Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Paris, France.
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24
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Zhang J, Shi P, Liu J, Li J, Cao Y. Efficacy and safety of iron chelator for transfusion-dependent patients with myelodysplastic syndrome: a meta-analysis. ACTA ACUST UNITED AC 2020; 24:669-678. [PMID: 31543071 DOI: 10.1080/16078454.2019.1666218] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
To systematically evaluate the efficacy and safety of iron chelators for transfusion-dependent patients with MDS. Thirteen cohort studies with 12,990 patients diagnosed with MDS were included in this study. According to m eta-analysis results transfusion-dependent MDS patients with secondary iron overload had a longer (HR = 0.52, 95%CI = 0.43-0.62, P < 0.001). Further subgroup analysis revealed a longer LFS (HR = 0.84, 95%CI = 0.76-0.93, P = 0.001) in MDS patients receiving iron chelators than in MDS patients not receiving iron chelators (HR = 0.52, 95%CI = 0.43-0.62, P < 0.001) and in patients with lower-risk MDS (HR = 0.50, 95%CI = 0.43-0.59, P < 0.001). Subgroup analysis of DFX showed that compared with patients not treated with iron chelators, the group receiving DFX monotherapy had significantly increased OS (HR = 0.43, 95%CI = 0.27-0.69, P < 0.001). In terms of tolerance, meta-analysis of binary variables in CAEs indicated that the occurrence of CAEs was significantly reduced by ICT (RR = 0.64, 95%CI = 0.57-0.71, P < 0.001).
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Affiliation(s)
- JingLing Zhang
- Department of Clinical Laboratory Examination, Fujian Medical University Union Hospital , Fuzhou , People's Republic of China
| | - Pengchong Shi
- Department of Clinical Laboratory Examination, Fujian Medical University Union Hospital , Fuzhou , People's Republic of China
| | - Jin Liu
- Department of Clinical Laboratory Examination, Fujian Medical University Union Hospital , Fuzhou , People's Republic of China
| | - Jinggang Li
- Fujian Provincial Key Laboratory on Hematology, Fujian Institute of Hematology, Fujian Medical University Union Hospital , Fuzhou , People's Republic of China
| | - Yingping Cao
- Department of Clinical Laboratory Examination, Fujian Medical University Union Hospital , Fuzhou , People's Republic of China
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25
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Liu YC, Illar GM, Bailey NG. Clinicopathologic characterisation of myeloid neoplasms with concurrent spliceosome mutations and myeloproliferative-neoplasm-associated mutations. J Clin Pathol 2020; 73:728-736. [PMID: 32217616 DOI: 10.1136/jclinpath-2020-206495] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 03/09/2020] [Accepted: 03/10/2020] [Indexed: 12/29/2022]
Abstract
AIMS Spliceosome genes (SF3B1, SRSF2, U2AF1 and ZRSR2) are commonly mutated in myeloid neoplasms, particularly in myelodysplastic syndromes (MDS). JAK2, MPL and CALR mutations are associated with myeloproliferative neoplasms (MPN). Although SF3B1 and MPN-associated mutations frequently co-occur in the rare entity MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), myeloid neoplasms with concurrent spliceosome and MPN-associated mutations encompass many disease entities and are not well characterised. METHODS Specimens from 2016 to 2019 with concurrent spliceosome and MPN-associated mutations were identified, and the clinicopathologic features were assessed. RESULTS The 36 cases were divided into mutational categories based on their spliceosome mutation. At diagnosis, cases with concurrent U2AF1 and MPN-associated mutations had lower leucocyte counts and platelet counts than did the other groups. Cases with mutant SRSF2 were more likely to have ASXL1 and IDH2 mutations, while U2AF1-mutated neoplasms were more likely to have an abnormal karyotype. The most common SF3B1 K700 and U2AF1 S34 mutational hotspots were underrepresented in our cohort of myeloid neoplasms with concurrent spliceosome and MPN-associated mutations, as SF3B1 and U2AF1 mutations tended to involve other codons. Numerous WHO-defined disease entities were represented in each spliceosome gene category; although MDS/MPN-RS-T were only identified in the group with SF3B1 mutations, they constituted only 1/4 of the neoplasms in the category. CONCLUSIONS Myeloid neoplasms with different mutant splicing factor and concurrent MPN-associated mutations demonstrate somewhat different clinical and pathologic features, but t he association between genotypes and phenotypes in these overlapping neoplasms is not straightforward.
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Affiliation(s)
- Yen-Chun Liu
- Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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26
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Stein EM, DiNardo CD, Pollyea DA, Schuh AC. Response Kinetics and Clinical Benefits of Nonintensive AML Therapies in the Absence of Morphologic Response. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2020; 20:e66-e75. [DOI: 10.1016/j.clml.2019.11.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 11/05/2019] [Accepted: 11/19/2019] [Indexed: 02/06/2023]
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27
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Kaphan E, Laurin D, Lafeuillade B, Drillat P, Park S. Impact of transfusion on survival in patients with myelodysplastic syndromes: Current knowledge, new insights and transfusion clinical practice. Blood Rev 2019; 41:100649. [PMID: 31918886 DOI: 10.1016/j.blre.2019.100649] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 10/25/2019] [Accepted: 12/05/2019] [Indexed: 02/01/2023]
Abstract
Red Blood Cell (RBC) transfusion dependence is a prevalent consequence of anaemia in patients with lower risk Myelodysplastic Syndromes (MDS). These patients have shorter survival compared to patients responding to Erythropoiesis-stimulating agents (ESA), raising the question of potential negative effects of chronic RBC transfusions on MDS prognosis, independently of IPSS-R. Besides commonly identified complications of transfusions like iron toxicity or cardiac events, oxidative stress could be a risk factor for ineffective haematopoiesis. Recently, physicochemical changes of RBC during storage have been described. These changes called storage lesions could play a role in immunomodulation in vivo. We review the currently identified sources of potential impact on transfusion-associated effects in MDS patients and we discuss the unexplored potential role of erythrocyte-derived-extracellular vesicles. They could amplify impairment of haematopoiesis in addition to the negative intrinsic effects underlying the pathology in MDS. Thus, chronic RBC transfusions appear to potentially impact the outcome of MDS.
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Affiliation(s)
- Eléonore Kaphan
- Service d'Hématologie, CHU de Grenoble, CS 10 217, Grenoble Cedex 09 38043, France.
| | - David Laurin
- Département scientifique, Etablissement Français du Sang Auvergne Rhône-Alpes, La Tronche, France; Institute for Advanced Biosciences, Equipe Pathologie Moléculaire des Cancers et Biomarqueurs, Université Grenoble Alpes, INSERM U1209 & CNRS UMR 5309, France
| | - Bruno Lafeuillade
- Service d'Hématologie, CHU de Grenoble, CS 10 217, Grenoble Cedex 09 38043, France
| | - Philippe Drillat
- Service d'Hématologie, CHU de Grenoble, CS 10 217, Grenoble Cedex 09 38043, France; Département scientifique, Etablissement Français du Sang Auvergne Rhône-Alpes, La Tronche, France
| | - Sophie Park
- Service d'Hématologie, CHU de Grenoble, CS 10 217, Grenoble Cedex 09 38043, France; Institute for Advanced Biosciences, Equipe Pathologie Moléculaire des Cancers et Biomarqueurs, Université Grenoble Alpes, INSERM U1209 & CNRS UMR 5309, France.
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28
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Zhao P, Qin J, Liu W, Quan R, Xiao H, Liu C, Li L, Lv Y, Zhu Q, Wang H, Guo X, Wang J, Hu X. Genetic alterations in 47 patients with a novel myelodysplastic syndrome diagnosis at a single center. Oncol Lett 2019; 18:5077-5084. [PMID: 31612018 PMCID: PMC6781645 DOI: 10.3892/ol.2019.10853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 06/19/2019] [Indexed: 11/23/2022] Open
Abstract
At least one mutation is present in 70–80% of patients with myelodysplastic syndrome (MDS). Genetic alterations and other molecular biological markers have been included in the diagnostic and treatment guidelines for MDS. The aim of the present study was to analyze the association between genetic alterations and clinicopathological features among 47 Chinese patients with a novel diagnosis of MDS using a next-generation sequencing approach. The results indicated that from the 47 patients, 66.0% had genetic alterations. Furthermore, seven genes, U2 small nuclear RNA auxiliary factor 1 (23.4%), splicing factor 3b subunit (12.8%), ASXL transcriptional regulator 1 (10.6%), tet methylcytosine dioxygenase 2 (8.5%), BCL6 corepressor (8.5%), TP53 (8.5%) and DNA methyltransferase 3α (6.4%), indicated a higher prevalence of alterations in >5% of patients. Among the 16 (51.6%) patients with ≥2 mutations, 12 (75%) had mutations in different genetic functional groups. Variant allele frequencies in signaling pathways were generally low, suggesting that mutations in the corresponding genes were acquired relatively late during the evolution of the leukemic clones. The mutation prevalence rates of Janus kinase 2 and SH2B adaptor protein 3 were significantly higher in the MDS unclassified group and in the very high-risk groups with a karyotype as a prognostic indicator, respectively (both P<0.05). The mutation prevalence rates of SET binding protein 1 and enhancer of zeste 2 polycomb repressive complex 2 subunit were significantly higher in the high-risk group (both P<0.05). In summary, 66.0% of the 47 patients with a novel MDS diagnosis had a genetic mutation as detected by 127-target gene next-generation sequencing. The results for the genetic alterations in the present study will supplement the database of patients with MDS in China.
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Affiliation(s)
- Pan Zhao
- Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China
| | - Jiayue Qin
- Annoroad Gene Technology Co., Ltd., Beijing 100176, P.R. China
| | - Weiyi Liu
- Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China
| | - Richeng Quan
- Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China
| | - Haiyan Xiao
- Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China
| | - Chi Liu
- Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China
| | - Liu Li
- Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China
| | - Yan Lv
- Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China
| | - Qianze Zhu
- Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China
| | - Hongzhi Wang
- Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China
| | - Xiaoqing Guo
- Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China
| | - Juan Wang
- Annoroad Gene Technology Co., Ltd., Beijing 100176, P.R. China
| | - Xiaomei Hu
- Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, P.R. China
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29
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Kimura K, Tabe Y, Ai T, Takehara I, Fukuda H, Takahashi H, Naito T, Komatsu N, Uchihashi K, Ohsaka A. A novel automated image analysis system using deep convolutional neural networks can assist to differentiate MDS and AA. Sci Rep 2019; 9:13385. [PMID: 31527646 PMCID: PMC6746738 DOI: 10.1038/s41598-019-49942-z] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 08/29/2019] [Indexed: 12/31/2022] Open
Abstract
Detection of dysmorphic cells in peripheral blood (PB) smears is essential in diagnostic screening of hematological diseases. Myelodysplastic syndromes (MDS) are hematopoietic neoplasms characterized by dysplastic and ineffective hematopoiesis, which diagnosis is mainly based on morphological findings of PB and bone marrow. We developed an automated diagnostic support system of MDS by combining an automated blood cell image-recognition system using a deep learning system (DLS) powered by convolutional neural networks (CNNs) with a decision-making system using extreme gradient boosting (XGBoost). The DLS of blood cell image-recognition has been trained using datasets consisting of 695,030 blood cell images taken from 3,261 PB smears including hematopoietic malignancies. The DLS simultaneously classified 17 blood cell types and 97 morphological features of such cells with >93.5% sensitivity and >96.0% specificity. The automated MDS diagnostic system successfully differentiated MDS from aplastic anemia (AA) with high accuracy; 96.2% of sensitivity and 100% of specificity (AUC 0.990). This is the first CNN-based automated initial diagnostic system for MDS using PB smears, which is applicable to develop new automated diagnostic systems for various hematological disorders.
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Affiliation(s)
- Konobu Kimura
- Department of Next Generation Hematology Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sysmex Corporation, Kobe, Japan
| | - Yoko Tabe
- Department of Next Generation Hematology Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan. .,Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
| | - Tomohiko Ai
- Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | | | - Hiroshi Fukuda
- Department of General Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hiromizu Takahashi
- Department of General Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Toshio Naito
- Department of General Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Norio Komatsu
- Department of Hematology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | | | - Akimichi Ohsaka
- Department of Next Generation Hematology Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University Graduate School of Medicine, Tokyo, Japan
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30
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Senturk Yikilmaz A, Akinci S, Bakanay ŞM, Dilek I. In myelodysplastic syndrome cases, what should be the level of ferritin which has prognostic value? Transfus Clin Biol 2019; 26:217-223. [PMID: 31420221 DOI: 10.1016/j.tracli.2019.07.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 07/23/2019] [Indexed: 11/19/2022]
Abstract
OBJECTIVES Myelodysplastic syndrome (MDS) is a highly mortal disease in which anemia is unresponsive to treatment. In this study, the effect of basal ferritin values on prognosis and survival was investigated in MDS patients without history of transfusion. METHODS Data were retrospectively analyzed for 62 MDS cases. The cases were divided into two groups according to ferritin values. RESULTS The mean survival time was 61.1±4.8 months. During the follow-up period, 34 (54.8%) patients deceased. Median ferritin level was 358ng/mL. The serum ferritin (SF) level associated with mortality was determined as 400ng/mL (ROC area for SF was 0.731 with a cutoff value of 400; sensitivity and specificity were 70.7% and 68.2%, respectively) (P=0.002). There were 29 (46.8%) patients with serum ferritin levels of ≥400ng/mL. Patients with serum ferritin levels≥400ng/mL had low survival rates. Ferritin≥400ng/mL was associated with six times increased mortality (P=0.001). CONCLUSION Although the acceptable ferritin level at the start of chelation therapy is 1000ng/mL, the fact that 400ng/mL value is associated with survival in our study suggests that it may be useful to start chelation therapy in the early period. Further case studies on the subject are required.
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Affiliation(s)
- A Senturk Yikilmaz
- Department of Hematology, Yildirım Beyazit University, 06010 Ankara, Turkey.
| | - S Akinci
- Department of Hematology, Ataturk Training and Research Hospital, 06010 Ankara, Turkey
| | - Ş M Bakanay
- Department of Hematology, Yildirım Beyazit University, 06010 Ankara, Turkey
| | - I Dilek
- Department of Hematology, Yildirım Beyazit University, 06010 Ankara, Turkey
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Jung KS, Kim YJ, Kim YK, Park SK, Kim HG, Kim SJ, Park J, Choi CW, Do YR, Kim I, Park S, Mun YC, Jeong SH, Kim MK, Yi HG, Chang MH, Kim SY, Lee JH, Jang JH. Clinical Outcomes of Decitabine Treatment for Patients With Lower-Risk Myelodysplastic Syndrome on the Basis of the International Prognostic Scoring System. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2019; 19:656-664. [PMID: 31375393 DOI: 10.1016/j.clml.2019.06.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 05/15/2019] [Accepted: 06/04/2019] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Decitabine has shown clinical benefits in patients with intermediate (INT)-2 or high-risk myelodysplastic syndrome (MDS), determined according to the International Prognostic Scoring System (IPSS), but the benefits have not been well demonstrated in patients with lower-risk (IPSS low or INT-1) disease. Recently, it was proposed that the prognosis for patients with IPSS lower-risk disease is heterogeneous, with a substantial proportion of these patients having poor survival. PATIENTS AND METHODS This study included patients with IPSS lower-risk MDS from the DRAMA (An Observational Study for Dacogen Long-Term Treatment in Patients With Myelodysplastic Syndrome; NCT01400633) and DIVA (A Study for Dacogen Treatment in Patients With Myelodysplastic Syndrome; NCT01041846) studies, which were prospective observational studies on the efficacy and safety of decitabine treatment in patients with MDS. Using the Lower-Risk Prognostic Scoring System [LR-PSS], we classified IPSS lower-risk MDS. Patients in each LR-PSS category were divided according to overall response (OR) to decitabine treatment, and survival outcomes were compared. RESULTS One hundred sixteen patients were enrolled: LR-PSS category 1 (n = 12; 10.3%), category 2 (n = 56; 48.3%), and category 3 (n = 48; 41.4%). Survival outcomes differed among the 3 categories (P = .046). The overall survival according to OR showed a significant difference in total patients (P = .008) and category 3 patients (P = .003). We analyzed predictive factors for OR, but no variable was found to significantly affect OR. CONCLUSION Decitabine treatment showed a survival benefit in the higher-risk group of IPSS lower-risk MDS patients who responded to treatment, and classification using the LR-PSS category was helpful for this subgroup, indicating that decitabine treatment might alter the natural course of disease in these patients.
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Affiliation(s)
- Ki Sun Jung
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Division of Hematology-Oncology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
| | - Yoo-Jin Kim
- Acute Leukemia Center, Seoul St Mary's Hematology Hospital, College of Medicine, Catholic University of Korea, Seoul, Korea
| | - Yeo-Kyeoung Kim
- Department of Hematology, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea
| | - Sung Kyu Park
- Department of Internal Medicine, Soonchunhyang University Hospital, Bucheon, Korea
| | - Hoon Gu Kim
- Division of Hematology and Oncology, Department of Internal Medicine, Gyeongnam Regional Cancer Center, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Soo Jeong Kim
- Division of Hematology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jinny Park
- Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
| | - Chul Won Choi
- Division of Oncology and Hematology, Department of Internal Medicine, Korea University Medical Center, Seoul, Korea
| | - Young Rok Do
- Division of Hematology-Oncology, School of Medicine, Keimyung University, Daegu, Korea
| | - Inho Kim
- Department of Internal Medicine, Seoul National University, Seoul, Korea
| | - Seonyang Park
- Department of Internal Medicine, Seoul National University, Seoul, Korea
| | - Yeung-Chul Mun
- Department of Hematology and Oncology, School of Medicine, Ewha Womans University, Seoul, Korea
| | - Seong Hyun Jeong
- Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea
| | - Min-Kyoung Kim
- Division of Oncology-Hematology, Department of Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Hyeon Gyu Yi
- Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea
| | - Myung Hee Chang
- Department of Hematology-Oncology, National Health Insurance Service Ilsan Hospital, Ilsan, Korea
| | - Su Youn Kim
- Medical Affairs, Janssen Korea, Seoul, Korea
| | - Je-Hwan Lee
- Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
| | - Jun Ho Jang
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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de Swart L, Crouch S, Hoeks M, Smith A, Langemeijer S, Fenaux P, Symeonidis A, Cermâk J, Hellström-Lindberg E, Stauder R, Sanz G, Mittelman M, Holm MS, Malcovati L, Mądry K, Germing U, Tatic A, Savic A, Almeida AM, Gredelj-Simec N, Guerci-Bresler A, Beyne-Rauzy O, Culligan D, Kotsianidis I, Itzykson R, van Marrewijk C, Blijlevens N, Bowen D, de Witte T. Impact of red blood cell transfusion dose density on progression-free survival in patients with lower-risk myelodysplastic syndromes. Haematologica 2019; 105:632-639. [PMID: 31171638 PMCID: PMC7049377 DOI: 10.3324/haematol.2018.212217] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 06/05/2019] [Indexed: 01/01/2023] Open
Abstract
Progression-free survival (PFS) of patients with lower-risk myelodysplastic syndromes (MDS) treated with red blood cell transfusions is usually reduced, but it is unclear whether transfusion dose density is an independent prognostic factor. The European MDS Registry collects prospective data at 6-monthly intervals from newly diagnosed lower-risk myelodysplastic syndromes patients in 16 European countries and Israel. Data on the transfusion dose density - the cumulative dose received at the end of each interval divided by the time since the beginning of the interval in which the first transfusion was received - were analyzed using proportional hazards regression with time-varying co-variates, with death and progression to higher-risk MDS/acute myeloid leukemia as events. Of the 1,267 patients included in the analyses, 317 died without progression; in 162 patients the disease had progressed. PFS was significantly associated with age, EQ-5D index, baseline World Health Organization classification, bone marrow blast count, cytogenetic risk category, number of cytopenias, and country. Transfusion dose density was inversely associated with PFS (P<1×10−4): dose density had an increasing effect on hazard until a dose density of 3 units/16 weeks. The transfusion dose density effect continued to increase beyond 8 units/16 weeks after correction for the impact of treatment with erythropoiesis-stimulating agents, lenalidomide and/or iron chelators. In conclusion, the negative effect of transfusion treatment on PFS already occurs at transfusion densities below 3 units/16 weeks. This indicates that transfusion dependency, even at relatively low dose densities, may be considered as an indicator of inferior PFS. This trial was registered at www.clinicaltrials.gov as #NCT00600860.
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Affiliation(s)
- Louise de Swart
- Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Simon Crouch
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK
| | - Marlijn Hoeks
- Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.,Center for Clinical Transfusion Research, Sanquin Research, Leiden, the Netherlands
| | - Alex Smith
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK
| | - Saskia Langemeijer
- Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Pierre Fenaux
- Service d'Hématologie, Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris and Université Paris 7, Paris, France
| | - Argiris Symeonidis
- Department of Medicine, Division of Hematology, University of Patras Medical School, Patras, Greece
| | - Jaroslav Cermâk
- Department of Clinical Hematology, Institute of Hematology & Blood Transfusion, Praha, Czech Republic
| | - Eva Hellström-Lindberg
- Department of Medicine, Division of Hematology, Karolinska Institutet, Stockholm, Sweden
| | - Reinhard Stauder
- Department of Internal Medicine V (Hematology and Oncology), Innsbruck Medical University, Innsbruck, Austria
| | - Guillermo Sanz
- Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Moshe Mittelman
- Department of Medicine A, Tel Aviv Sourasky (Ichilov) Medical Center and Sackler Medical Faculty, Tel Aviv University, Tel Aviv, Israel
| | - Mette Skov Holm
- Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
| | - Luca Malcovati
- Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | - Krzysztof Mądry
- Department of Hematology, Oncology and Internal Medicine, Warsaw Medical University, Warsaw, Poland
| | - Ulrich Germing
- Department of Hematology, Oncology and Clinical Immunology, Universitatsklinik Düsseldorf, Düsseldorf, Germany
| | - Aurelia Tatic
- Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - Aleksandar Savic
- Clinic of Hematology - Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | | | - Njetocka Gredelj-Simec
- Department of Internal Medicine, Division of Hematology, Merkur University Hospital, Zagreb, Croatia
| | - Agnes Guerci-Bresler
- Service d'Hématologie, Centre Hospitalier Universitaire (CHU) Brabois Vandoeuvre, Nancy, France
| | - Odile Beyne-Rauzy
- Service de Médecine Interne, IUCT-Oncopole, CHU Toulouse, Toulouse, France
| | - Dominic Culligan
- Department of Haematology, Aberdeen Royal Infirmary, Aberdeen, UK
| | - Ioannis Kotsianidis
- Department of Hematology, Democritus University of Thrace Medical School, University Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Raphael Itzykson
- Service d'Hématologie, Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris and Université Paris 7, Paris, France
| | - Corine van Marrewijk
- Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Nicole Blijlevens
- Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - David Bowen
- St. James's Institute of Oncology, Leeds Teaching Hospitals, Leeds, UK
| | - Theo de Witte
- Department of Tumor Immunology - Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
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Park S, Baek DW, Sohn SK, Ahn JS, Kim HJ, Shin HJ, Chung JS, Lee SM, Lee WS, Lim SN, Lee YJ, Choi Y, Lee HS, Cho YY, Lee GW, Moon JH. Favorable Outcomes With Tumor Burden Reduction Following Administration of Hypomethylating Agents Before Allogeneic Hematopoietic Cell Transplantation in Patients With Higher Risk Myelodysplastic Syndrome. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2019; 19:e367-e373. [PMID: 31060990 DOI: 10.1016/j.clml.2019.03.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 02/17/2019] [Accepted: 03/17/2019] [Indexed: 01/13/2023]
Abstract
INTRODUCTION The clinical significance of tumor burden reduction following administration of hypomethylating agents (HMAs) for transplant-eligible patients with higher risk myelodysplastic syndrome (MDS) was evaluated. PATIENTS AND METHODS Data of 79 transplant-eligible patients (< 65 years) diagnosed with higher-risk MDS between July 2002 and March 2013 were retrospectively analyzed. Among 79 patients, 30 (38%) underwent allogeneic hematopoietic cell transplantation (HCT group), and 49 (62%) were treated with HMA alone (non-HCT group). RESULTS The median follow-up duration was 732 days (range, 28-1952 days), and the 3-year overall survival (OS) rate of all patients was 30.6%. In the HCT group, early HCT showed a better 3-year OS rate than late HCT (67.1% vs. 25.7%; P = .035). In multivariate analysis, time/performance of allogenic transplant (no HCT vs. early HCT, hazard ratio, 0.18; 95% confidence interval, 0.04-0.81; P = .026) and follow-up higher risk International Prognostic Scoring System (hazard ratio, 6.22; 95% confidence interval, 2.09-18.51; P = .001) were significantly correlated with OS. CONCLUSION To predict the clinical outcomes of patients with higher risk MDS, the optimal time for tumor burden evaluation is prior to follow-up rather than at the time of initial diagnosis. Patients with lower International Prognostic Scoring System risk groups after HMA treatment or early HCT had favorable OS.
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Affiliation(s)
- Sungwoo Park
- Department of Internal Medicine, Gyeongsang National University Hospital, College of Medicine, Gyeongsang National University, Jinju, Korea
| | - Dong Won Baek
- Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Sang Kyun Sohn
- Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jae-Sook Ahn
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, School of Medicine, Chonnam National University, Hwasun, Republic of Korea
| | - Hyeoung-Joon Kim
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, School of Medicine, Chonnam National University, Hwasun, Republic of Korea
| | - Ho Jin Shin
- Department of Hematology-Oncology, Pusan National University Hospital, School of Medicine, Pusan National University, Busan, Republic of Korea
| | - Joo Seop Chung
- Department of Hematology-Oncology, Pusan National University Hospital, School of Medicine, Pusan National University, Busan, Republic of Korea
| | - Sang Min Lee
- Department of Hematology-Oncology, Busan Paik Hospital, Busan, Republic of Korea
| | - Won Sik Lee
- Department of Hematology-Oncology, Busan Paik Hospital, Busan, Republic of Korea
| | - Sung Nam Lim
- Department of Hematology-Oncology, Haewoondae Paik Hospital, Busan, Republic of Korea
| | - Yoo Jin Lee
- Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Yunsuk Choi
- Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Ho Sup Lee
- Department of Hematology-Oncology, Kosin University Gospel Hospital, Busan, Republic of Korea
| | - Yoon Young Cho
- Department of Hematology-Oncology, Daegu Catholic University Medical Center, Daegu, Republic of Korea
| | - Gyeong-Won Lee
- Department of Internal Medicine, Gyeongsang National University Hospital, College of Medicine, Gyeongsang National University, Jinju, Korea
| | - Joon Ho Moon
- Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
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Du M, Zhou F, Jin R, Hu Y, Mei H. Mutations in the DNA methylation pathway predict clinical efficacy to hypomethylating agents in myelodysplastic syndromes: a meta-analysis. Leuk Res 2019; 80:11-18. [DOI: 10.1016/j.leukres.2019.03.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 02/22/2019] [Accepted: 03/01/2019] [Indexed: 11/27/2022]
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Clinical, histopathological and molecular characterization of hypoplastic myelodysplastic syndrome. Leukemia 2019; 33:2495-2505. [PMID: 30940907 DOI: 10.1038/s41375-019-0457-1] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 02/22/2019] [Accepted: 03/14/2019] [Indexed: 11/08/2022]
Abstract
Diagnostic criteria for hypoplastic myelodysplasic syndrome (h-MDS) have not been clearly established, making the differential diagnosis from other bone marrow failure syndromes (BMF) challenging. In this study, we aimed to delineate clinical, histopathological, and molecular features of h-MDS, based on a large and well-annotated cohort of patients with bone marrow (BM) hypocellularity. The study included 534 consecutive adult patients with hypocellular BM (278 h-MDS and 136 aplastic anemia), and 727 with normo- or hypercellular MDS (n-MDS). Comparison of clinical features of patients with h-MDS as defined by BM cellularity ≤25% (n = 204) or reduced age-adjusted cellularity (n = 74) did not reveal significant differences. We developed a diagnostic score to discriminate h-MDS from non-malignant BMF based on histological and cytological variables with the highest specificity for MDS (h-score). The information from chromosomal abnormalities and somatic mutation patterns was then integrated into a cyto-histological/genetic score (hg-score). This score was able to segregate two groups of h-MDS with a significantly different risk of blast progression (P < 0.001). The integration of cyto-histological and genetic features in adult patients with hypocellular BM facilitated segregation into two distinct groups, one with clinical and genetic features highly consistent with myeloid neoplasm, and one with features more consistent with non-malignant BMF.
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36
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Rydén J, Clements M, Hellström-Lindberg E, Höglund P, Edgren G. A longer duration of red blood cell storage is associated with a lower hemoglobin increase after blood transfusion: a cohort study. Transfusion 2019; 59:1945-1952. [PMID: 30793325 DOI: 10.1111/trf.15215] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 01/28/2019] [Accepted: 01/30/2019] [Indexed: 01/07/2023]
Abstract
BACKGROUND RBC concentrates are commonly stored for up to 42 days but there has been conflicting evidence on the effect of storage duration and clinical outcomes. Most clinical studies have focused on possible associations between duration of storage time and risk for adverse outcomes, including mortality. Recent clinical trials did not find any such associations, but fewer studies have addressed whether storage time affects component efficacy. The main aim of this study was to determine the effect of RBC storage time on hemoglobin increment in transfused patients. STUDY DESIGN AND METHODS Transfusion data on a cohort of patients with myelodysplastic syndromes were linked to hemoglobin measurements taken between 2 days before and 28 days after a transfusion episode. We applied a mixed-effect linear regression model, accounting for patient characteristics and time from transfusion to next hemoglobin measurement, to study the effect of RBC storage on the hemoglobin increment. RESULTS The study population consisted of 225 patients who received 6437 RBC units. Compared to units stored less than 5 days, transfusion of blood units stored 5 to 9, 10 to 19, 20 to 29, or 30 or more days resulted in hemoglobin increases that were 0.83 (95% confidence interval [CI], 0.24-1.41), 0.92 (95% CI, 0.34-1.51), 1.33 (95% CI, 0.65-2.02) and 1.51 (95% CI, 0.58-2.43) g/L lower, respectively, per RBC unit. Results were consistent in sensitivity analyses. CONCLUSIONS Longer RBC storage was associated with a smaller increase in hemoglobin concentration after transfusion. Although statistically significant, the effect was modest, and its clinical relevance in subgroups of patients should be investigated in prospective clinical trials.
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Affiliation(s)
- Jenny Rydén
- Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.,Hematology Center, Karolinska University Hospital, Stockholm, Sweden
| | - Mark Clements
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Eva Hellström-Lindberg
- Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.,Hematology Center, Karolinska University Hospital, Stockholm, Sweden
| | - Petter Höglund
- Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Gustaf Edgren
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Department of Cardiology, Södersjukhuset, Stockholm, Sweden
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Prominence of nestin-expressing Schwann cells in bone marrow of patients with myelodysplastic syndromes with severe fibrosis. Int J Hematol 2019; 109:309-318. [PMID: 30632058 DOI: 10.1007/s12185-018-02576-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 12/05/2018] [Accepted: 12/10/2018] [Indexed: 10/27/2022]
Abstract
Nestin-expressing stromal cells (NESCs) and Schwann cells in the bone marrow (BM) play crucial roles as a niche for normal hematopoietic stem cells in mice. It has been reported that both types of cells are decreased in myeloproliferative neoplasms in patients and also in a mouse model, whereas an increase in NESCs was reported in acute myeloid leukemia. It is thus of interest whether and how these BM stromal cells are structured in myelodysplastic syndromes (MDS). Here, we focused on NESCs and glial fibrillary acidic protein (GFAP)-expressing cells in the BM of MDS patients. We found a marked increase of NESCs in MDS with fibrosis (MDS-F) at a high frequency (9/19; 47.4%), but not in MDS without fibrosis (0/26; 0%). Intriguingly, in eight of the nine (88.9%) MDS-F cases with elevated NESCs, a majority of NESCs also expressed GFAP, with an additional increase in GFAP single-positive cells. Furthermore, in seven of them, we found a prominent structure characterized by neurofilament heavy chain staining surrounded by NESCs with GFAP expression. This structure may represent peripheral nerve axons surrounded by Schwann cells, and could be relevant to the pathophysiology of MDS-F.
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38
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Gardikas N, Vikentiou M, Konsta E, Kontos CK, Papageorgiou SG, Spathis A, Bazani E, Bouchla A, Kapsimali V, Psarra K, Foukas P, Dimitriadis G, Pappa V. Immunophenotypic Profile of CD34+ Subpopulations and Their Role in the Diagnosis and Prognosis of Patients with De-Novo, Particularly Low-Grade Myelodysplastic Syndromes. CYTOMETRY PART B-CLINICAL CYTOMETRY 2018; 96:73-82. [DOI: 10.1002/cyto.b.21725] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 06/20/2018] [Accepted: 06/29/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Nikolaos Gardikas
- Second Department of Internal Medicine and Research Institute; University General Hospital Attikon; Haidari Greece
| | - Myrofora Vikentiou
- Second Department of Internal Medicine and Research Institute; University General Hospital Attikon; Haidari Greece
| | - Evgenia Konsta
- Second Department of Internal Medicine and Research Institute; University General Hospital Attikon; Haidari Greece
| | - Christos K. Kontos
- Department of Biochemistry and Molecular Biology; National and Kapodistrian University of Athens; Panepistimiopolis, Athens Greece
| | - Sotirios G. Papageorgiou
- Second Department of Internal Medicine and Research Institute; University General Hospital Attikon; Haidari Greece
| | - Aris Spathis
- 2nd Department of Pathology, School of Medicine; University of Athens, University General Hospital Attikon; Haidari Greece
| | - Efthimia Bazani
- Second Department of Internal Medicine and Research Institute; University General Hospital Attikon; Haidari Greece
| | - Anthi Bouchla
- Second Department of Internal Medicine and Research Institute; University General Hospital Attikon; Haidari Greece
| | - Violetta Kapsimali
- Department of Dermatology and Venereology; HIV/AIDS Unit, Andreas Syggros Hospital; Athens Greece
| | - Katherina Psarra
- Department of Immunology and Histocompatibility; Evangelismos Hospital; Athens Greece
| | - Periklis Foukas
- 2nd Department of Pathology, School of Medicine; University of Athens, University General Hospital Attikon; Haidari Greece
| | - George Dimitriadis
- Second Department of Internal Medicine and Research Institute; University General Hospital Attikon; Haidari Greece
| | - Vasiliki Pappa
- Second Department of Internal Medicine and Research Institute; University General Hospital Attikon; Haidari Greece
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39
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Tang Y, Zhang X, Han S, Chu T, Qi J, Wang H, Tang X, Qiu H, Fu C, Ruan C, Wu D, Han Y. Prognostic Significance of Platelet Recovery in Myelodysplastic Syndromes With Severe Thrombocytopenia. Clin Appl Thromb Hemost 2018; 24:217S-222S. [PMID: 30296835 PMCID: PMC6714828 DOI: 10.1177/1076029618802363] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Severe thrombocytopenia is a serious condition that frequently arises in patients
with myelodysplastic syndrome (MDS) and is associated with poor prognosis. Few
studies have investigated the prognostic significance of platelet recovery in
patients with MDS having thrombocytopenia. We retrospectively analyzed 117
patients with de novo MDS complicated with thrombocytopenia (platelet count
[PLT] < 100 × 109/L). Patients received decitabine treatment
(schedule A) or decitabine followed by allogeneic hematopoietic stem cell
transplantation (allo-HSCT; schedule B). Severe thrombocytopenia (PLT < 20 ×
109/L), identified in 31 (26.5%) patients, was associated with
poor survival. The PLT increased significantly after decitabine treatment in the
2 groups. Patients with thrombocytopenia treated with schedule B showed a
superior prognosis compared to those treated with schedule A. On analysis of
overall survival by platelet response in patients with severe thrombocytopenia,
a significant survival advantage was observed in patients who achieved a
platelet response, who would further benefit from allo-HSCT following decitabine
therapy. The results indicate a potentially favorable prognostic impact of
platelet response achieved with decitabine. Patients with MDS having severe
thrombocytopenia may benefit from the effective recovery of platelets and
further allo-HSCT following decitabine therapy.
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Affiliation(s)
- Yaqiong Tang
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Collaborative Innovation Center of Hematology of Soochow University, Suzhou, China.,Institute of Blood and Marrow Transplantation, Suzhou, China.,Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Xinyou Zhang
- Department of Hematology, Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Jinan University, Shenzhen, Guangdong Province, China
| | - Shiyu Han
- Institute of Blood and Marrow Transplantation, Suzhou, China.,Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Tiantian Chu
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Collaborative Innovation Center of Hematology of Soochow University, Suzhou, China.,Institute of Blood and Marrow Transplantation, Suzhou, China.,Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Jiaqian Qi
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Collaborative Innovation Center of Hematology of Soochow University, Suzhou, China.,Institute of Blood and Marrow Transplantation, Suzhou, China.,Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Hong Wang
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Collaborative Innovation Center of Hematology of Soochow University, Suzhou, China.,Institute of Blood and Marrow Transplantation, Suzhou, China.,Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Xiaowen Tang
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Collaborative Innovation Center of Hematology of Soochow University, Suzhou, China.,Institute of Blood and Marrow Transplantation, Suzhou, China.,Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Huiying Qiu
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Collaborative Innovation Center of Hematology of Soochow University, Suzhou, China.,Institute of Blood and Marrow Transplantation, Suzhou, China.,Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Chengcheng Fu
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Collaborative Innovation Center of Hematology of Soochow University, Suzhou, China.,Institute of Blood and Marrow Transplantation, Suzhou, China.,Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Changgeng Ruan
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Collaborative Innovation Center of Hematology of Soochow University, Suzhou, China.,Institute of Blood and Marrow Transplantation, Suzhou, China.,Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Depei Wu
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Collaborative Innovation Center of Hematology of Soochow University, Suzhou, China.,Institute of Blood and Marrow Transplantation, Suzhou, China.,Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Yue Han
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Collaborative Innovation Center of Hematology of Soochow University, Suzhou, China.,Institute of Blood and Marrow Transplantation, Suzhou, China.,Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
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40
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Bastida JM, López-Godino O, Vicente-Sánchez A, Bonanad-Boix S, Xicoy-Cirici B, Hernández-Sánchez JM, Such E, Cervera J, Caballero-Berrocal JC, López-Cadenas F, Arnao-Herráiz M, Rodríguez I, Llopis-Calatayud I, Jiménez MJ, Del Cañizo-Roldán MC, Díez-Campelo M. Hidden myelodysplastic syndrome (MDS): A prospective study to confirm or exclude MDS in patients with anemia of uncertain etiology. Int J Lab Hematol 2018; 41:109-117. [PMID: 30290085 DOI: 10.1111/ijlh.12933] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 08/30/2018] [Accepted: 09/07/2018] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Diagnosis of myelodysplastic syndromes (MDSs) when anemia is the only abnormality can be complicated. The aim of our study was to investigate the primary causes of anemia and/or macrocytosis of uncertain etiology. METHODS We conducted a multicenter, prospective study over 4 months in three hematology laboratories. In step 1, we used an automated informatics system to screen 137 453 hemograms for cases of anemia and/or macrocytosis (n = 2702). In step 2, we excluded all patients whose anemia appeared to be due to a known cause. This left 290 patients had anemia of uncertain etiology. In step 3, we conducted further investigations, including a peripheral blood smear, and analysis of iron, vitamin B12, folate, and thyroid hormone levels. RESULTS A differential diagnosis was obtained in 139 patients (48%). The primary causes of anemia were iron deficiency (n = 59) and megaloblastic anemia (n = 39). In total, 25 hematologic disorders were diagnosed, including 14 patients with MDS (56%). The median age of MDS patients was 80 years, 12 had anemia as an isolated cytopenia, and most (n = 10) had lower-risk disease (IPSS-R ≤ 3.5). SF3B1 mutations were most frequent (n = 6) and correlated with the presence of ring sideroblasts (100%) and associated with better prognosis (P = 0.001). CONCLUSIONS Our prospective, four-step approach is an efficient and logical strategy to facilitate the diagnosis of MDS on the basis of unexplained anemia and/or macrocytosis, and may allow the early diagnosis of the most serious causes of anemia. Molecular analysis of genes related to MDS could be a promising diagnostic and prognostic approach.
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Affiliation(s)
| | | | | | | | - Blanca Xicoy-Cirici
- Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Badalona, Spain
| | - Jesus M Hernández-Sánchez
- Instituto de Investigacion Biomedica de Salamanca, IBMCC, Centro de Investigacion del Cancer, Universidad de Salamanca-CSIC, Salamanca, Spain
| | - Esperanza Such
- Hematology, Laboratorio de Citogenética y Biología Molecular, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Jose Cervera
- Hematology, Laboratorio de Citogenética y Biología Molecular, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | | | | | | | - Inés Rodríguez
- Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Badalona, Spain
| | | | - María J Jiménez
- Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Badalona, Spain
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41
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Benton CB, Khan M, Sallman D, Nazha A, Nogueras González GM, Piao J, Ning J, Aung F, Al Ali N, Jabbour E, Kadia TM, Borthakur G, Ravandi F, Pierce S, Steensma D, DeZern A, Roboz G, Sekeres M, Andreeff M, Kantarjian H, Komrokji RS, Garcia-Manero G. Prognosis of patients with intermediate risk IPSS-R myelodysplastic syndrome indicates variable outcomes and need for models beyond IPSS-R. Am J Hematol 2018; 93:1245-1253. [PMID: 30051599 DOI: 10.1002/ajh.25234] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 07/18/2018] [Accepted: 07/23/2018] [Indexed: 01/01/2023]
Abstract
The International Prognostic Scoring System-Revised (IPSS-R) is one standard for myelodysplastic syndrome (MDS) risk stratification. It divides patients into five categories including an intermediate subset (IPSS-R int-risk). Outcomes and clinical interventions for patients with IPSS-R int-risk are not well defined. We performed an analysis of outcomes of this group of patients. Out of 3167 patients, a total of 298 were identified with IPSS-R int-risk MDS and retrospectively analyzed to assess characteristics affecting outcomes. Cox proportional hazard models for overall survival (OS) were performed to identify statistically significant clinical factors that influence survival. Age of 66 years or greater, peripheral blood blasts of 2% or more, and history of red blood cell (RBC) transfusion were significantly associated with inferior survival. Based on these features, MDS patients with IPSS-R int-risk were classified into two prognostic risk groups for analysis, an int-favorable group and an int-adverse group, and had significantly divergent outcomes. Sequential prognostication was validated using two independent datasets comprising over 700 IPSS-R int-risk patients. The difference in median survival between int-favorable and int-adverse patients was 3.7 years in the test cohort, and 1.8 and 2.0 years in the two validation cohorts. These results confirm significantly variable outcomes of patients with IPSS-R int-risk and need for different prognostic systems.
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Affiliation(s)
- Christopher B. Benton
- Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - Maliha Khan
- Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - David Sallman
- Department of Malignant Hematology; H. Lee Moffitt Cancer Center; Tampa Florida
| | - Aziz Nazha
- Department of Leukemia; Cleveland Clinic; Cleveland Ohio
| | | | - Jin Piao
- Department of Statistics; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - Jing Ning
- Department of Statistics; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - Fleur Aung
- Laboratory Medicine; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - Najla Al Ali
- Department of Malignant Hematology; H. Lee Moffitt Cancer Center; Tampa Florida
| | - Elias Jabbour
- Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - Tapan M. Kadia
- Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - Gautam Borthakur
- Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - Farhad Ravandi
- Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - Sherry Pierce
- Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - David Steensma
- Department of Medical Oncology; Dana-Farber Cancer Institute; Boston
| | - Amy DeZern
- Sidney Kimmel Comprehensive Cancer Center; The Johns Hopkins University School of Medicine; Baltimore Maryland
| | - Gail Roboz
- Joan and Sanford I. Weill Department of Medicine; Weill Cornell Medical; New York New York
| | | | - Michael Andreeff
- Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - Hagop Kantarjian
- Department of Leukemia; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - Rami S. Komrokji
- Department of Malignant Hematology; H. Lee Moffitt Cancer Center; Tampa Florida
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42
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Rydén J, Edgren G, Karimi M, Walldin G, Tobiasson M, Wikman A, Hellström-Lindberg E, Höglund P. Male sex and the pattern of recurrent myeloid mutations are strong independent predictors of blood transfusion intensity in patients with myelodysplastic syndromes. Leukemia 2018; 33:522-527. [PMID: 30267009 DOI: 10.1038/s41375-018-0256-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 07/23/2018] [Accepted: 08/07/2018] [Indexed: 01/29/2023]
Affiliation(s)
- Jenny Rydén
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.,Hematology Center, Karolinska University Hospital, Stockholm, Sweden
| | - Gustaf Edgren
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Department of Cardiology, Södersjukhuset, Stockholm, Sweden
| | - Mohsen Karimi
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Gunilla Walldin
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Magnus Tobiasson
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.,Hematology Center, Karolinska University Hospital, Stockholm, Sweden
| | - Agneta Wikman
- Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.,Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Eva Hellström-Lindberg
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.,Hematology Center, Karolinska University Hospital, Stockholm, Sweden
| | - Petter Höglund
- Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. .,Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
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43
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Lin P, Ren Y, Yan X, Luo Y, Zhang H, Kesarwani M, Bu J, Zhan D, Zhou Y, Tang Y, Zhu S, Xu W, Zhou X, Mei C, Ma L, Ye L, Hu C, Azam M, Ding W, Jin J, Huang G, Tong H. The high NRF2 expression confers chemotherapy resistance partly through up-regulated DUSP1 in myelodysplastic syndromes. Haematologica 2018; 104:485-496. [PMID: 30262569 PMCID: PMC6395322 DOI: 10.3324/haematol.2018.197749] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 09/26/2018] [Indexed: 11/15/2022] Open
Abstract
Although cytarabine has been widely considered as one of the chemotherapy drugs for high-risk myelodysplastic syndromes (MDS), the overall response rate is only approximately 20-30%. Nuclear factor erythroid 2-related factor 2 (NRF2, also called NFE2L2) has been shown to play a pivotal role in preventing cancer cells from being affected by chemotherapy. However, it is not yet known whether NRF2 can be used as a prognostic biomarker in MDS, or whether elevated NRF2 levels are associated with cytarabine resistance. Here, we found that NRF2 expression levels in bone marrow from high-risk patients exceeded that of low-risk MDS patients. Importantly, high NRF2 levels are correlated with inferior outcomes in MDS patients (n=137). Downregulation of NRF2 by the inhibitor Luteolin, or lentiviral shRNA knockdown, enhanced the chemotherapeutic efficacy of cytarabine, while MDS cells treated by NRF2 agonist Sulforaphane showed increased resistance to cytarabine. More importantly, pharmacological inhibition of NRF2 could sensitize primary high-risk MDS cells to cytarabine treatment. Mechanistically, downregulation of dual specificity protein phosphatase 1, an NRF2 direct target gene, could abrogate cytarabine resistance in NRF2 elevated MDS cells. Silencing NRF2 or dual specificity protein phosphatase 1 also significantly sensitized cytarabine treatment and inhibited tumors in MDS cells transplanted mouse models in vivo. Our study suggests that targeting NRF2 in combination with conventional chemotherapy could pave the way for future therapy for high-risk MDS.
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Affiliation(s)
- Peipei Lin
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Yanling Ren
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaomei Yan
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Yingwan Luo
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Hua Zhang
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Meenu Kesarwani
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Jiachen Bu
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Di Zhan
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Yile Zhou
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Yuting Tang
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Shuanghong Zhu
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Weilai Xu
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xinping Zhou
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Chen Mei
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Liya Ma
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Li Ye
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Chao Hu
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Mohammad Azam
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Wei Ding
- Department of Pathology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jie Jin
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Gang Huang
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Hongyan Tong
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China .,Institute of Hematology, Zhejiang University, Hangzhou, China.,Myelodysplastic Syndromes Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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44
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Lin P, Luo Y, Zhu S, Maggio D, Yang H, Hu C, Wang J, Zhang H, Ren Y, Zhou X, Mei C, Ma L, Xu W, Ye L, Zhuang Z, Jin J, Tong H. Isocitrate dehydrogenase 2 mutations correlate with leukemic transformation and are predicted by 2-hydroxyglutarate in myelodysplastic syndromes. J Cancer Res Clin Oncol 2018; 144:1037-1047. [PMID: 29549529 DOI: 10.1007/s00432-018-2627-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 03/12/2018] [Indexed: 12/01/2022]
Abstract
PURPOSE The myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by the presence of somatically mutated hematopoietic stem cells (HSCs) that increase the risk of progression to secondary acute myeloid leukemia (sAML). Mutations in isocitrate dehydrogenase (IDHmut) are thought to correlate with the increased production of the oncogenic protein 2-hydroxyglutarate (2-HG) in AML. The aim of this study was to examine whether serum 2-HG has utility as a prognostic biomarker, and whether elevated 2-HG levels are predictive of IDH mutations in patients with MDS. METHODS Genetic profiling was utilized to determine the genetic composition of a large cohort of MDS patients, including the presence or absence of IDH1 or IDH2 mutations (n = 281). Serum 2-HG levels were detected by liquid chromatography-tandem mass spectrometry. RESULTS In the current study of MDS patients, elevated serum 2-HG levels were predictive of inferior overall- and leukemia-free survival irrespective of IPSS risk grouping. Higher serum 2-HG levels predicted the presence of IDH mutations. IDH2mut patients had a higher risk of leukemic transformation. The co-occurrence of DNMT3A or SRSF2 mutations was found to be increased in IDH2mut patients. IDH2 mutations were associated with significantly worse OS and LFS amongst patients with low-risk MDS by IPSS grouping. CONCLUSIONS The noted predictive value of serum 2-HG levels and IDH2 mutations on OS and LFS support the use of biomarkers and/or underlying cytogenetics in novel prognostic scoring systems for MDS.
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MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Cohort Studies
- Female
- Glutarates/blood
- Humans
- Isocitrate Dehydrogenase/genetics
- Leukemia, Myeloid, Acute/blood
- Leukemia, Myeloid, Acute/enzymology
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/pathology
- Male
- Middle Aged
- Mutation
- Myelodysplastic Syndromes/blood
- Myelodysplastic Syndromes/enzymology
- Myelodysplastic Syndromes/genetics
- Myelodysplastic Syndromes/pathology
- Prognosis
- Young Adult
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Affiliation(s)
- Peipei Lin
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Yingwan Luo
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Shuanghong Zhu
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Dominic Maggio
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Haiyang Yang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Chao Hu
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Jinghan Wang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Hua Zhang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Yanling Ren
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Xinping Zhou
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Chen Mei
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Liya Ma
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Weilai Xu
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Li Ye
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Zhengping Zhuang
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Hongyan Tong
- Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China.
- Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
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Li W, Schnatter AR. Benzene risk assessment: does new evidence on myelodysplastic syndrome justify a new approach? Crit Rev Toxicol 2018; 48:417-432. [DOI: 10.1080/10408444.2018.1437389] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Affiliation(s)
- Wenchao Li
- Occupational and Public Health Division, ExxonMobil Biomedical Sciences Inc., Annandale, NJ, USA
- Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - A. Robert Schnatter
- Occupational and Public Health Division, ExxonMobil Biomedical Sciences Inc., Annandale, NJ, USA
- EpiSolutions, LLC, Easton, PA, USA
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Asada N. Regulation of Malignant Hematopoiesis by Bone Marrow Microenvironment. Front Oncol 2018; 8:119. [PMID: 29740536 PMCID: PMC5924781 DOI: 10.3389/fonc.2018.00119] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 04/03/2018] [Indexed: 12/19/2022] Open
Abstract
Hematopoietic stem cells (HSCs) that give rise to all kinds of hematopoietic lineage cells on various demands throughout life are maintained in a specialized microenvironment called “niche” in the bone marrow (BM). Defining niche cells and unveiling its function have been the subject of intense study, and it is becoming increasingly clear how niche cells regulate HSCs in normal hematopoiesis. Leukemia stem cells (LSCs), which are able to produce leukemic cells and maintain leukemic clones, are assumed to share common features with healthy HSCs. Accumulating evidence suggests that LSCs reside in a specialized BM microenvironment; moreover, LSCs could control and rebuild the microenvironment to enhance their progression and survival. This article discusses the recent advances in our knowledge of the microenvironment supporting malignant hematopoiesis, including LSC niche.
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Affiliation(s)
- Noboru Asada
- Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan
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Management of anemia in low-risk myelodysplastic syndromes treated with erythropoiesis-stimulating agents newer and older agents. Med Oncol 2018; 35:76. [DOI: 10.1007/s12032-018-1135-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 04/12/2018] [Indexed: 10/17/2022]
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Kim SY, Park Y, Kim H, Kim J, Kwon GC, Koo SH. Discriminating myelodysplastic syndrome and other myeloid malignancies from non-clonal disorders by multiparametric analysis of automated cell data. Clin Chim Acta 2018; 480:56-64. [PMID: 29378171 DOI: 10.1016/j.cca.2018.01.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 12/19/2017] [Accepted: 01/18/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND We investigated the usefulness of novel complete blood count (CBC) data for discriminating myeloid malignancies from non-clonal CBC abnormalities. METHODS Data were obtained during routine CBC tests of 119 samples from 37 myelodysplastic syndrome (MDS) patients, 92 samples from 45 myeloproliferative neoplasm (MPN) patients, and 15 samples from 11 chronic myelogenous leukemia (CML) patients using a DxH800 (Beckman Coulter). Data obtained from patients with hypocellular bone marrow and from those with other non-clonal diseases with CBC abnormalities were included in the comparisons. RESULTS For cell population data of neutrophils, the means of median, upper median, lower median, and low angle light scatters were significantly lower in MDS patients than in patients without hematological malignancies. Low hemoglobin density (LHD) did not significantly differ between the MDS and non-clonal cytopenia patients, but it was significantly higher in the MPN and CML patients. We selected 13 parameters and scored the MDS diagnosis using cut-off values obtained from receiver operating characteristic (ROC) curve analysis. Using a score > 9, MDS was distinguished from non-clonal cytopenia with a sensitivity of 92.4% and a specificity of 85.4%. CONCLUSIONS Multiparametric analyses of new automated parameters are useful for discriminating MDS from non-clonal cytopenia.
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Affiliation(s)
- Seon Young Kim
- Department of Laboratory Medicine, Chungnam National University School of Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea; Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
| | - Yumi Park
- Department of Laboratory Medicine, Chungnam National University School of Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Hyunjin Kim
- Department of Laboratory Medicine, Chungnam National University School of Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Jimyung Kim
- Department of Laboratory Medicine, Chungnam National University School of Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Gye Cheol Kwon
- Department of Laboratory Medicine, Chungnam National University School of Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Sun Hoe Koo
- Department of Laboratory Medicine, Chungnam National University School of Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
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Huang J, Wang Z, Huang L, Zheng M. CD41 immune staining of micromegakaryocytes improves the diagnosis of myelodysplastic syndrome and differentiation from pancytopenia. Leuk Res 2018; 66:15-19. [PMID: 29353154 DOI: 10.1016/j.leukres.2017.10.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Revised: 10/15/2017] [Accepted: 10/17/2017] [Indexed: 12/24/2022]
Abstract
A morphometric analysis was performed on aspirated clots of bone marrow to identify the presence of micromegakaryocytes after immune staining with a monoclonal antibody raised against CD41. Quantitative and qualitative abnormalities of micromegakaryocytes were assessed based on both standard staining and CD41 immune staining. Micromegakaryocytes were largely detected in bone marrow from patients with myelodysplastic syndrome (MDS), while almost no micromegakaryocytes were present in aplastic anemia. CD41 immune staining clearly improved the efficiency of micromegakaryocyte detection under any conditions, showing strong potential as a tool for the auxiliary diagnosis of MDS and differentiation of MDS from pancytopenia, particularly aplastic anemia(AA).
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Affiliation(s)
- Jinjin Huang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiqiong Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lifang Huang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Miao Zheng
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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