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1
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Gong X, Zhai X, Shen Q, Gale RP, Chen J. Challenges determining the best target duration of deep molecular response after which to attempt achieving therapy-free remission in chronic myeloid leukaemia. Leukemia 2025; 39:810-815. [PMID: 40000844 PMCID: PMC11976291 DOI: 10.1038/s41375-025-02540-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/25/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025]
Affiliation(s)
- Xiaowen Gong
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Xiaolin Zhai
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Qiujin Shen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Robert Peter Gale
- Centre for Haematology, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK
| | - Junren Chen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- Tianjin Institutes of Health Science, Tianjin, China.
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Kwaśnik P, Kiełbus M, Zaleska J, Link-Lenczowska D, Zawada M, Wysogląd H, Sacha T, Giannopoulos K. The PD1 Molecule May Contribute to Lower Treatment-Free Remission Rates in Patients with Chronic Myeloid Leukemia with the e13a2 Transcript. J Clin Med 2025; 14:2304. [PMID: 40217754 PMCID: PMC11989261 DOI: 10.3390/jcm14072304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 03/21/2025] [Accepted: 03/24/2025] [Indexed: 04/14/2025] Open
Abstract
Background/Objectives: Chronic myeloid leukemia (CML) is characterized by the presence of the BCR::ABL1 fusion gene, most commonly in the e14a2 or e13a2 variants. Studies show that the transcript type in CML may be important for achieving treatment-free remission (TFR). This study aimed to immunologically characterize CML patients with e13a2 and e14a2 transcripts to search for differences that may contribute to achieving remission in patients after therapy withdrawal. Methods: Using multicolor flow cytometry, we analyzed the differences in the immune system at the time of imatinib discontinuation and the early stage of TFR in fifty-one CML patients with different transcripts. RQ-PCR and ddPCR were used to monitor the dynamics of BCR::ABL1 transcript changes. The patients were grouped using principal component analysis (PCA) based on the percentage of detected immune cells that were classified as populations consistently selected by the MCFS-ID algorithm from randomly selected data. Results: PCA separated CML patients into two groups defined by k-means clustering, indicating significant heterogeneity within the studied population. We found a significant association between Cluster metrics (Cluster 1 and 2) and BCR::ABL1 transcript types (e13a2 or e14a2) (p = 0.003, 95% CI: 0.026-0.595, OR = 0.14, Fisher test). The e13a2 transcript was less frequent in Cluster 2 than in Cluster 1, while e14a2 was more common in Cluster 2. Additionally, patients grouped into Cluster 1 had significantly higher percentages of the PD1 expressing populations cDC PD1+, CD56dimCD16+PD1+, CD8+PD1+, CD4+PD1+, and CD19+PD1+, as identified by the MCFS-ID algorithm, compared to patients in Cluster 2. Conclusions: Our results suggest that immunological differences may be related to the BCR::ABL1 transcript type, which could affect the number of active CML cells represented by the BCR::ABL1 transcript amount and thus may determine molecular recurrence.
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Affiliation(s)
- Paulina Kwaśnik
- Department of Experimental Hematooncology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Michał Kiełbus
- Department of Experimental Hematooncology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Joanna Zaleska
- Department of Experimental Hematooncology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Dorota Link-Lenczowska
- Diagnostic Department of Hematology and Genetics, The University Hospital in Kraków, 30-688 Kraków, Poland
| | - Magdalena Zawada
- Diagnostic Department of Hematology and Genetics, The University Hospital in Kraków, 30-688 Kraków, Poland
| | - Hubert Wysogląd
- Department of Hematology, University Hospital in Kraków, 30-688 Kraków, Poland
| | - Tomasz Sacha
- Department of Hematology, University Hospital in Kraków, 30-688 Kraków, Poland
- Department of Hematology, Jagiellonian University Medical College in Kraków, 31-008 Kraków, Poland
| | - Krzysztof Giannopoulos
- Department of Experimental Hematooncology, Medical University of Lublin, 20-093 Lublin, Poland
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Saisaard W, Owattanapanich W. Comparative analysis of BCR::ABL1 p210 mRNA transcript quantification and ratio to ABL1 control gene converted to the International Scale by chip digital PCR and droplet digital PCR for monitoring patients with chronic myeloid leukemia. Clin Chem Lab Med 2024; 0:cclm-2024-0456. [PMID: 39167824 DOI: 10.1515/cclm-2024-0456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024]
Abstract
OBJECTIVES Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome, leading to the BCR::ABL1 fusion gene and hyper-proliferation of granulocytes. Tyrosine kinase inhibitors (TKIs) are effective, and minimal residual disease (MRD) monitoring is crucial. Digital PCR platforms offer increased precision compared to quantitative PCR but lack comparative studies. METHODS Eighty CML patient samples were analyzed in parallel using digital droplet PCR (ddPCR) (QXDx™ BCR-ABL %IS Kit) and chip digital PCR (cdPCR) (Dr. PCR™ BCR-ABL1 Major IS Detection Kit). RESULTS Overall, qualitative and quantitative agreement was good. Sensitivity analysis showed positive percentage agreement and negative percentage agreement were both ≥90 %, and the quadratic weighted kappa index for molecular response (MR) level categorization was 0.94 (95 %CI 0.89, 0.98). MR levels subgroup analysis showed perfect categorical agreement on MR level at MR3 or above, while 35.4 % (17/48) of patient samples with MR4 or below showed discordant categorizations. Overall, Lin's concordance correlation coefficient (CCC) for the ratio of %BCR::ABL1/ABL1 converted to the International Scale (BCR::ABL1 IS) was almost perfect quantitative agreement (Lin's CCC=0.99). By subgroups of MR levels, Lin's CCC showed a quantitative agreement of BCR::ABL1 IS decreased as MR deepened. CONCLUSIONS Both cdPCR and ddPCR demonstrated comparable performance in detecting BCR::ABL1 transcripts with high concordance in MR3 level or above. Choosing between platforms may depend on cost, workflow, and sensitivity requirements.
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Affiliation(s)
- Wannachai Saisaard
- Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Weerapat Owattanapanich
- Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Center of Excellence of Siriraj Adult Acute Myeloid/Lymphoblastic Leukemia (SiAML), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Chavaro-Francisco G, Hernández-Zavala A, Bravo-Cidro CE, Rios-Rodriguez S, Muciño-Sánchez M, López-López M, Castro-Martínez XH, Olarte-Carrillo I, Garcia-Laguna A, Barranco-Lampón G, De la Cruz-Rosas A, Martínez-Tovar A, Córdova EJ. Gene Variants in Components of the microRNA Processing Pathway in Chronic Myeloid Leukemia. Genes (Basel) 2024; 15:1054. [PMID: 39202414 PMCID: PMC11353722 DOI: 10.3390/genes15081054] [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: 07/02/2024] [Revised: 08/06/2024] [Accepted: 08/08/2024] [Indexed: 09/03/2024] Open
Abstract
Current therapy in chronic myeloid leukemia (CML) has improved patient life expectancy close to that of healthy individuals. However, molecular alterations other than BCR::ABL1 fusion gene in CML are barely known. MicroRNAs are important regulators of gene expression, and variants in some of the components of microRNA biosynthesis pathways have been associated with genetic susceptibility to different types of cancer. Thus, the aim of this study was to evaluate the association of variants located in genes involved in the biogenesis of microRNAs with susceptibility to CML. Fifteen variants in eight genes involved in the biogenesis of miRNAs were genotyped in 296 individuals with CML and 485 healthy participants using TaqMan probes. The association of gene variants with CML and clinical variables was evaluated by a Chi-square test, and odds ratios and 95% confidence intervals were estimated by logistic regression. The variant rs13078 in DICER1 was significantly higher among CML individuals than in healthy participants. In addition, the variants rs7813 and rs2740349 were significantly associated with worse prognosis, according to their Hasford scores, whereas the rs2740349 variant was also associated with a later age at diagnosis. These findings suggest that variants in components of the microRNA biogenesis pathway could be involved in CML genetic risk.
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Affiliation(s)
- Guillermina Chavaro-Francisco
- Section of Research and Postgraduate Studies, Superior School of Medicine, National Institute Polytechique, Mexico City 11340, Mexico; (G.C.-F.); (A.H.-Z.)
- Oncogenomics Consortium Laboratory, Clinic Research Department, National Institute of Genomic Medicine, Mexico City 14610, Mexico; (C.E.B.-C.); (S.R.-R.); (M.M.-S.)
| | - Araceli Hernández-Zavala
- Section of Research and Postgraduate Studies, Superior School of Medicine, National Institute Polytechique, Mexico City 11340, Mexico; (G.C.-F.); (A.H.-Z.)
| | - Camila E. Bravo-Cidro
- Oncogenomics Consortium Laboratory, Clinic Research Department, National Institute of Genomic Medicine, Mexico City 14610, Mexico; (C.E.B.-C.); (S.R.-R.); (M.M.-S.)
- Department of Biological Systems, Metropolitan Autonomous University, Campus Xochimilco, Mexico City 04960, Mexico;
| | - Sandybel Rios-Rodriguez
- Oncogenomics Consortium Laboratory, Clinic Research Department, National Institute of Genomic Medicine, Mexico City 14610, Mexico; (C.E.B.-C.); (S.R.-R.); (M.M.-S.)
- Department of Biological Systems, Metropolitan Autonomous University, Campus Xochimilco, Mexico City 04960, Mexico;
| | - Mabel Muciño-Sánchez
- Oncogenomics Consortium Laboratory, Clinic Research Department, National Institute of Genomic Medicine, Mexico City 14610, Mexico; (C.E.B.-C.); (S.R.-R.); (M.M.-S.)
- School of Biology, Metropolitan Autonomous University, Campus Xochimilco, Mexico City 04960, Mexico
| | - Marisol López-López
- Department of Biological Systems, Metropolitan Autonomous University, Campus Xochimilco, Mexico City 04960, Mexico;
| | - Xóchitl H. Castro-Martínez
- Genomics of Psychiatric and Neurogenerative Diseases Laboratory, National Institute of Genomic Medicine, Mexico City 14610, Mexico;
| | - Irma Olarte-Carrillo
- Molecular Biology Laboratory, Service of Hematology, Hospital General de Mexico, “Dr. Eduardo Liceaga”, Mexico City 06720, Mexico; (I.O.-C.); (A.G.-L.); (G.B.-L.); (A.M.-T.)
| | - Anel Garcia-Laguna
- Molecular Biology Laboratory, Service of Hematology, Hospital General de Mexico, “Dr. Eduardo Liceaga”, Mexico City 06720, Mexico; (I.O.-C.); (A.G.-L.); (G.B.-L.); (A.M.-T.)
| | - Gilberto Barranco-Lampón
- Molecular Biology Laboratory, Service of Hematology, Hospital General de Mexico, “Dr. Eduardo Liceaga”, Mexico City 06720, Mexico; (I.O.-C.); (A.G.-L.); (G.B.-L.); (A.M.-T.)
| | - Adrián De la Cruz-Rosas
- Molecular Biology Laboratory, Service of Hematology, Hospital General de Mexico, “Dr. Eduardo Liceaga”, Mexico City 06720, Mexico; (I.O.-C.); (A.G.-L.); (G.B.-L.); (A.M.-T.)
| | - Adolfo Martínez-Tovar
- Molecular Biology Laboratory, Service of Hematology, Hospital General de Mexico, “Dr. Eduardo Liceaga”, Mexico City 06720, Mexico; (I.O.-C.); (A.G.-L.); (G.B.-L.); (A.M.-T.)
| | - Emilio J. Córdova
- Oncogenomics Consortium Laboratory, Clinic Research Department, National Institute of Genomic Medicine, Mexico City 14610, Mexico; (C.E.B.-C.); (S.R.-R.); (M.M.-S.)
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Zeng J, Liang X, Duan L, Tan F, Chen L, Qu J, Li J, Li K, Luo D, Hu Z. Targeted disruption of the BCR-ABL fusion gene by Cas9/dual-sgRNA inhibits proliferation and induces apoptosis in chronic myeloid leukemia cells. Acta Biochim Biophys Sin (Shanghai) 2024; 56:525-537. [PMID: 38414349 DOI: 10.3724/abbs.2023280] [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] [Indexed: 02/29/2024] Open
Abstract
The BCR-ABL fusion gene, formed by the fusion of the breakpoint cluster region protein ( BCR) and the Abl Oncogene 1, Receptor Tyrosine Kinase ( ABL) genes, encodes the BCR-ABL oncoprotein, which plays a crucial role in leukemogenesis. Current therapies have limited efficacy in patients with chronic myeloid leukemia (CML) because of drug resistance or disease relapse. Identification of novel strategies to treat CML is essential. This study aims to explore the efficiency of novel CRISPR-associated protein 9 (Cas9)/dual-single guide RNA (sgRNA)-mediated disruption of the BCR-ABL fusion gene by targeting BCR and cABL introns. A co-expression vector for Cas9 green fluorescent protein (GFP)/dual-BA-sgRNA targeting BCR and cABL introns is constructed to produce lentivirus to affect BCR-ABL expression in CML cells. The effects of dual-sgRNA virus-mediated disruption of BCR-ABL are analyzed via the use of a genomic sequence and at the protein expression level. Cell proliferation, cell clonogenic ability, and cell apoptosis are assessed after dual sgRNA virus infection, and phosphorylated BCR-ABL and its downstream signaling molecules are detected. These effects are further confirmed in a CML mouse model via tail vein injection of Cas9-GFP/dual-BA-sgRNA virus-infected cells and in primary cells isolated from patients with CML. Cas9-GFP/dual-BA-sgRNA efficiently disrupts BCR-ABL at the genomic sequence and gene expression levels in leukemia cells, leading to blockade of the BCR-ABL tyrosine kinase signaling pathway and disruption of its downstream molecules, followed by cell proliferation inhibition and cell apoptosis induction. This method prolongs the lifespan of CML model mice. Furthermore, the effect is confirmed in primary cells derived from patients with CML.
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MESH Headings
- Animals
- Humans
- Mice
- Apoptosis/genetics
- Cell Proliferation/genetics
- CRISPR-Cas Systems
- Fusion Proteins, bcr-abl/genetics
- Fusion Proteins, bcr-abl/metabolism
- Genes, abl
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy
- Proto-Oncogene Proteins c-bcr/genetics
- Proto-Oncogene Proteins c-bcr/metabolism
- RNA, Guide, CRISPR-Cas Systems
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Affiliation(s)
- Jianling Zeng
- Translational Medicine Institute, the First People's Hospital of Chenzhou, Hengyang Medical School, University of South China, Chenzhou 423000, China
- The First Affiliated Hospital of Xiangnan University, Chenzhou 423000, China
| | - Xinquan Liang
- Translational Medicine Institute, the First People's Hospital of Chenzhou, Hengyang Medical School, University of South China, Chenzhou 423000, China
- The First Affiliated Hospital of Xiangnan University, Chenzhou 423000, China
| | - Lili Duan
- Translational Medicine Institute, the First People's Hospital of Chenzhou, Hengyang Medical School, University of South China, Chenzhou 423000, China
- The First Affiliated Hospital of Xiangnan University, Chenzhou 423000, China
| | - Fenghua Tan
- Translational Medicine Institute, the First People's Hospital of Chenzhou, Hengyang Medical School, University of South China, Chenzhou 423000, China
- The First Affiliated Hospital of Xiangnan University, Chenzhou 423000, China
| | - Liujie Chen
- Translational Medicine Institute, the First People's Hospital of Chenzhou, Hengyang Medical School, University of South China, Chenzhou 423000, China
- The First Affiliated Hospital of Xiangnan University, Chenzhou 423000, China
| | - Jiayao Qu
- Translational Medicine Institute, the First People's Hospital of Chenzhou, Hengyang Medical School, University of South China, Chenzhou 423000, China
| | - Jia Li
- Translational Medicine Institute, the First People's Hospital of Chenzhou, Hengyang Medical School, University of South China, Chenzhou 423000, China
- The First Affiliated Hospital of Xiangnan University, Chenzhou 423000, China
| | - Kai Li
- Translational Medicine Institute, the First People's Hospital of Chenzhou, Hengyang Medical School, University of South China, Chenzhou 423000, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Dixian Luo
- Department of Laboratory Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Shenzhen 518000, China
| | - Zheng Hu
- Translational Medicine Institute, the First People's Hospital of Chenzhou, Hengyang Medical School, University of South China, Chenzhou 423000, China
- The First Affiliated Hospital of Xiangnan University, Chenzhou 423000, China
- National & Local Joint Engineering Laboratory for High-through Molecular Diagnosis Technology, the First People's Hospital of Chenzhou, Chenzhou 423000, China
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6
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Kwaśnik P, Zaleska J, Link-Lenczowska D, Zawada M, Wysogląd H, Ochrem B, Bober G, Wasilewska E, Hus I, Szarejko M, Prejzner W, Grzybowska-Izydorczyk O, Klonowska-Szymczyk A, Mędraś E, Kiełbus M, Sacha T, Giannopoulos K. High Level of CD8 +PD-1 + Cells in Patients with Chronic Myeloid Leukemia Who Experienced Loss of MMR after Imatinib Discontinuation. Cells 2024; 13:723. [PMID: 38667336 PMCID: PMC11048908 DOI: 10.3390/cells13080723] [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: 03/29/2024] [Revised: 04/12/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024] Open
Abstract
Treatment-free remission (TFR) is achieved in approximately half of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The mechanisms responsible for TFR maintenance remain elusive. This study aimed to identify immune markers responsible for the control of residual CML cells early in the TFR (at 3 months), which may be the key to achieving long-term TFR and relapse-free survival (RFS) after discontinuation of imatinib. Our study included 63 CML patients after imatinib discontinuation, in whom comprehensive analysis of changes in the immune system was performed by flow cytometry, and changes in the BCR::ABL1 transcript levels were assessed by RQ-PCR and ddPCR. We demonstrated a significant increase in the percentage of CD8+PD-1+ cells in patients losing TFR. The level of CD8+PD-1+ cells is inversely related to the duration of treatment and incidence of deep molecular response (DMR) before discontinuation. Analysis of the ROC curve showed that the percentage of CD8+PD-1+ cells may be a significant factor in early molecular recurrence. Interestingly, at 3 months of TFR, patients with the e13a2 transcript had a significantly higher proportion of the PD-1-expressing immune cells compared to patients with the e14a2. Our results suggest the important involvement of CD8+PD-1+ cells in the success of TFR and may help in identifying a group of patients who could successfully discontinue imatinib.
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MESH Headings
- Humans
- Imatinib Mesylate/therapeutic use
- Imatinib Mesylate/pharmacology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/drug effects
- Female
- Male
- Middle Aged
- Adult
- Programmed Cell Death 1 Receptor/metabolism
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Aged
- Fusion Proteins, bcr-abl/genetics
- Fusion Proteins, bcr-abl/metabolism
- Young Adult
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Affiliation(s)
- Paulina Kwaśnik
- Department of Experimental Hematooncology, Medical University of Lublin, 20-093 Lublin, Poland; (P.K.)
| | - Joanna Zaleska
- Department of Experimental Hematooncology, Medical University of Lublin, 20-093 Lublin, Poland; (P.K.)
| | - Dorota Link-Lenczowska
- Department of Hematology Diagnostics, Jagiellonian University Hospital in Kraków, 30-688 Kraków, Poland
| | - Magdalena Zawada
- Department of Hematology Diagnostics, Jagiellonian University Hospital in Kraków, 30-688 Kraków, Poland
| | - Hubert Wysogląd
- Department of Hematology, Jagiellonian University Hospital in Kraków, 30-688 Kraków, Poland
| | - Bogdan Ochrem
- Department of Hematology, Jagiellonian University Hospital in Kraków, 30-688 Kraków, Poland
| | - Grażyna Bober
- Department of Hematooncology and Bone Marrow Transplantation, School of Medicine in Katowice, Medical University of Silesia, 40-032 Katowice, Poland
| | - Ewa Wasilewska
- Department of Hematology, Medical University of Białystok, 15-276 Białystok, Poland
| | - Iwona Hus
- Department of Hematology, Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland
- Department of Clinical Transplantology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Monika Szarejko
- Department of Hematology and Transplantology, Medical University of Gdańsk, 80-214 Gdańsk, Poland
| | - Witold Prejzner
- Department of Hematology and Transplantology, Medical University of Gdańsk, 80-214 Gdańsk, Poland
| | | | | | - Ewa Mędraś
- Department of Hematology, Neoplastic Blood Disorders and Bone Marrow Transplantation in Wrocław, 50-367 Wrocław, Poland
| | - Michał Kiełbus
- Department of Experimental Hematooncology, Medical University of Lublin, 20-093 Lublin, Poland; (P.K.)
| | - Tomasz Sacha
- Chair of Hematology, Jagiellonian University Medical College in Kraków, 31-501 Kraków, Poland
| | - Krzysztof Giannopoulos
- Department of Experimental Hematooncology, Medical University of Lublin, 20-093 Lublin, Poland; (P.K.)
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7
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Marcé S, Méndez A, Xicoy B, Estrada N, Cabezón M, Sturla AL, García MR, Angona A, Amat P, Escribano Serrat S, Scalzulli E, Morgades M, Senín A, Hernández-Boluda JC, Ferrer-Marín F, Anguita E, Cortés M, Plensa E, Breccia M, García-Gutierrez V, Zamora L. e14a2 Transcript Favors Treatment-Free Remission in Chronic Myeloid Leukemia When Associated with Longer Treatment with Tyrosine Kinase Inhibitors and Sustained Deep Molecular Response. J Clin Med 2024; 13:779. [PMID: 38337473 PMCID: PMC10856594 DOI: 10.3390/jcm13030779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/24/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
e13a2 and e14a2 are the most frequent transcript types of the BCR::ABL1 fusion gene in chronic myeloid leukemia (CML). The current goal with tyrosine kinase inhibitors (TKI) is to achieve sustained deep molecular response (DMR) in order to discontinue TKI treatment and remain in the so-called treatment-free remission (TFR) phase, but biological factors associated with these goals are not well established. This study aimed to determine the effect of transcript type on TFR in patients receiving frontline treatment with imatinib (IM) or second-generation TKI (2G-TKI). Patients treated at least 119 months with IM presented less post-discontinuation relapse than those that discontinued IM before 119 months (p = 0.005). In addition, cases with the e14a2 transcript type treated at least 119 months with IM presented a better TFR (p = 0.024). On the other hand, the type of transcript did not affect the cytogenetic or molecular response in 2G-TKI treated patients; however, the use of 2G-TKI may be associated with higher and earlier DMR in patients with the e14a2 transcript.
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Affiliation(s)
- Sílvia Marcé
- Hematology Department, Myeloid Neoplasms Group, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (A.M.); (B.X.); (N.E.); (M.C.); (M.M.); (L.Z.)
| | - Aleix Méndez
- Hematology Department, Myeloid Neoplasms Group, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (A.M.); (B.X.); (N.E.); (M.C.); (M.M.); (L.Z.)
| | - Blanca Xicoy
- Hematology Department, Myeloid Neoplasms Group, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (A.M.); (B.X.); (N.E.); (M.C.); (M.M.); (L.Z.)
| | - Natalia Estrada
- Hematology Department, Myeloid Neoplasms Group, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (A.M.); (B.X.); (N.E.); (M.C.); (M.M.); (L.Z.)
| | - Marta Cabezón
- Hematology Department, Myeloid Neoplasms Group, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (A.M.); (B.X.); (N.E.); (M.C.); (M.M.); (L.Z.)
| | - Antonella Luciana Sturla
- Hematology Department, ICO Hospitalet-Hospital Duran y Reynals, 08908 Barcelona, Spain; (A.L.S.); (M.R.G.); (A.S.)
| | - Miriam Ratia García
- Hematology Department, ICO Hospitalet-Hospital Duran y Reynals, 08908 Barcelona, Spain; (A.L.S.); (M.R.G.); (A.S.)
| | - Anna Angona
- Hematology Department, ICO Girona-Hospital Josep Trueta, 17007 Girona, Spain;
| | - Paula Amat
- Hematology Department, Hospital Clínico Universitario-INCLIVA de Valencia, 46010 Valencia, Spain; (P.A.); (J.C.H.-B.)
| | - Silvia Escribano Serrat
- Hematology Department, Hospital Clínico San Carlos, IML, IdISSC, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (S.E.S.); (E.A.)
| | - Emilia Scalzulli
- Hematology, Department of Precision and Translational Medicine, Policlinico Umberto 1, Sapienza University, 00189 Rome, Italy; (E.S.); (M.B.)
| | - Mireia Morgades
- Hematology Department, Myeloid Neoplasms Group, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (A.M.); (B.X.); (N.E.); (M.C.); (M.M.); (L.Z.)
| | - Alicia Senín
- Hematology Department, ICO Hospitalet-Hospital Duran y Reynals, 08908 Barcelona, Spain; (A.L.S.); (M.R.G.); (A.S.)
| | - Juan Carlos Hernández-Boluda
- Hematology Department, Hospital Clínico Universitario-INCLIVA de Valencia, 46010 Valencia, Spain; (P.A.); (J.C.H.-B.)
| | - Francisca Ferrer-Marín
- Hematology Department, Hospital General Universitario Morales Meseguer-CIBERER, IMIB, UCAM, 30008 Múrcia, Spain;
| | - Eduardo Anguita
- Hematology Department, Hospital Clínico San Carlos, IML, IdISSC, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (S.E.S.); (E.A.)
| | - Montserrat Cortés
- Hematology Department, Hospital General de Granollers, 08402 Granollers, Spain;
| | - Esther Plensa
- Hematology Department, Consorci Sanitari del Maresme, Hospital de Mataró, 08301 Mataró, Spain;
| | - Massimo Breccia
- Hematology, Department of Precision and Translational Medicine, Policlinico Umberto 1, Sapienza University, 00189 Rome, Italy; (E.S.); (M.B.)
| | - Valentín García-Gutierrez
- Hematology Department, Hospital Ramón y Cajal, IRYCIS, Universidad de Alcalalá Madrid, 28801 Madrid, Spain;
| | - Lurdes Zamora
- Hematology Department, Myeloid Neoplasms Group, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (A.M.); (B.X.); (N.E.); (M.C.); (M.M.); (L.Z.)
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Park H, Kim HJ, Sohn SK, Baik Y, Kim D, Lee SY, Kong JH, Kim H, Shin DY, Ahn JS, Park J, Park S, Kim I. Effect of BCR::ABL1 transcript type and droplet digital polymerase chain reaction on successful treatment-free remission in chronic myeloid leukemia patients who discontinued tyrosine kinase inhibitor. Ther Adv Hematol 2023; 14:20406207231205637. [PMID: 37929079 PMCID: PMC10624046 DOI: 10.1177/20406207231205637] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 09/05/2023] [Indexed: 11/07/2023] Open
Abstract
Background Droplet digital polymerase chain reaction (ddPCR) is an exact method of measurement. Objectives We conducted this study to identify the prognostic factors for successful treatment-free remission in patients with chronic-phase chronic myeloid leukemia who discontinued tyrosine kinase inhibitors (TKIs). We also aimed to validate ddPCR for predicting molecular relapse. Design This is a prospective, multicenter study. Methods We enrolled patients treated with TKIs for at least 3 years with a confirmed sustained deep molecular response (DMR) for at least 1 year. TKI was re-administered in patients who experienced the loss of major molecular response (MMR). Results A total of 66 patients from five institutions in South Korea were enrolled. During a median follow-up period of 16.5 months, 29/66 (43.9%) patients experienced molecular relapse; the probability of molecular relapse-free survival (RFS) at 6 or 12 months after TKI discontinuation was 65.6% or 57.8%, respectively, with most molecular relapses occurring within the first 7 months. All patients who lost MMR were re-treated with TKI, and all re-achieved MMR at a median of 2.8 months. E14a2 transcript type (p = 0.005) and longer DMR duration (⩾48 months) prior to TKI discontinuation (p = 0.002) were associated with prolonged molecular RFS and with sustained DMR. Patients with both e13a2 transcript type and detectable BCR::ABL1 (⩾MR5.0) by ddPCR at the time of TKI discontinuation showed shorter duration of molecular RFS (p = 0.015). Conclusion Our data suggest that transcript type and BCR::ABL1 transcript levels on ddPCR should be taken into consideration when deciding whether to discontinue TKI therapy.
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Affiliation(s)
- Hyunkyung Park
- Department of Internal Medicine, Seoul National University–Seoul Metropolitan Government Boramae Medical Center, Seoul, South Korea
| | - Hyeong-Joon Kim
- Department of Internal Medicine, Chonnam National University, Hwasun Hospital, Hwasun, South Korea
| | - Sang-Kyun Sohn
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, South Korea
| | | | | | | | - Jee Hyun Kong
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, South Korea
| | - Hawk Kim
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, South Korea
| | - Dong-Yeop Shin
- Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jae-Sook Ahn
- Department of Internal Medicine, Chonnam National University, Hwasun Hospital, Hwasun, South Korea
| | - Jinny Park
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, South Korea
| | - Seonyang Park
- Department of Internal Medicine, Inje University, Haeundae Paik Hospital, Busan, South Korea
| | - Inho Kim
- Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, 101, Daehak-ro, Jongno-gu, Seoul 03080, South Korea
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9
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Gou X, Zhang Y, Zhu S, Yu X, Qin L, Cheng X, Zhang Y, Ding S, Chen R, Tang H, Cheng W. Asymmetric Hairpins DNA Encapsulated Silver Nanoclusters for In Situ Fluorescence Imaging of Fusion Gene Isoforms in Bone Marrow. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2303034. [PMID: 37365695 DOI: 10.1002/smll.202303034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/30/2023] [Indexed: 06/28/2023]
Abstract
Rapid and accurate imaging of the BCR/ABL fusion gene isoforms (e.g., e13a2, e14a2 and co-expression type) of chronic myeloid leukemia (CML) is of vital importance to first-line drug selection, but there is no assay that meets clinical needs (e.g., clinical kits > 18 h without isoforms information). Herein, an in situ imaging platform is developed for the rapid and accurate detection of CML fusion gene isoforms using asymmetric sequence-enhanced hairpins DNA encapsulated silver nanoclusters (ADHA) and catalyzed hairpin assembly (CHA). The specific detection of e13a2 and e14a2 fusion gene isoforms with detection limits of 19.2 am (11.558 copies µL-1 ) and 32.56 am (19.601 copies µL-1 ) in one-pot is achieved. The feasibility of the developed assay for real-world applications are demonstrated by one-step fluorescence imaging (40 min) of e13a2, e14a2 and co-expression type in bone marrow quantitatively (International Standard: 15.66%-168.878%) and further validated by cDNA-sequencing. This work suggests that the developed imaging platform holds great potential for rapid identification of the fusion gene isoforms and isoform related treatment monitoring.
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MESH Headings
- Humans
- Fusion Proteins, bcr-abl/genetics
- Fusion Proteins, bcr-abl/therapeutic use
- Bone Marrow
- Silver/therapeutic use
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Protein Isoforms/genetics
- DNA, Complementary
- Optical Imaging
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Affiliation(s)
- Xiaolong Gou
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Yangli Zhang
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Shasha Zhu
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Xiaolin Yu
- Department of Laboratory Medicine, Zigong Fourth People's Hospital, Sichuan, 643000, P. R. China
| | - Lu Qin
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Xiaoxue Cheng
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Yuhong Zhang
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Shijia Ding
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Rui Chen
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Hua Tang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Wei Cheng
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
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10
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de Castro Alves CE, Bogza SL, Bohdan N, Rozhenko AB, de Freitas Gomes A, de Oliveira RC, de Azevedo RG, Maciel LRS, Dhyani A, Grafov A, Pontes GS. Pharmacological assessment of the antineoplastic and immunomodulatory properties of a new spiroindolone derivative (7',8'-Dimethoxy-1',3'-dimethyl-1,2,3',4'-tetrahydrospiro[indole-3,5'-pyrazolo[3,4-c]isoquinolin]-2-one) in chronic myeloid leukemia. Invest New Drugs 2023; 41:629-637. [PMID: 37452982 DOI: 10.1007/s10637-023-01382-3] [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: 05/09/2023] [Accepted: 07/11/2023] [Indexed: 07/18/2023]
Abstract
The discovery and development of effective novel compounds is paramount in oncology for improving cancer therapy. In this study, we developed a new derivative of spiroindolone (7',8'-Dimethoxy-1',3'-dimethyl-1,2,3',4'-tetrahydrospiro[indole-3,5'- pyrazolo[3,4-c]isoquinolin]-2-one) and evaluated its anticancer- and immunomodulatory potential in a vitro model of chronic leukemia. We utilized the chronic leukemia cell line K562, as well as non-cancerous peripheral blood mononuclear cells (PBMC) and Vero cells (kidney epithelium of Cercopithecus aethiops). We assessed the cytotoxicity of the compound using the MTT assay, and performed cell cycle assays to determine its impact on different stages of the cell cycle. To evaluate its antineoplastic activity, we conducted a colony formation test to measure the effect of the compound on the clonal growth of cancer cells. Furthermore, we evaluated the immunomodulatory activity of the compound by measuring the levels of pro and anti-inflammatory cytokines. The study findings demonstrate that the spiroindolone-derived compound exerted noteworthy cytotoxic effects against K562 cells, with an IC50 value of 25.27 µg/mL. Additionally, it was observed that the compound inhibited the clonal proliferation of K562 cells while displaying minimal toxicity to normal cells. The compound exhibited its antiproliferative activity by inducing G2/M cell cycle arrest, preventing the entry of K562 cells into mitosis. Notably, the compound demonstrated an immunomodulatory effect by upregulating the production of cytokines IL-6 and IL-12/23p40. In conclusion, the spiroindolone-derived compound evaluated in this study has demonstrated significant potential as a therapeutic agent for the treatment of chronic myeloid leukemia. Further investigations are warranted to explore its clinical applications.
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Affiliation(s)
- Carlos Eduardo de Castro Alves
- Post-Graduate Program in Basic and Applied Immunology, Institute of Biological Science, Federal University of Amazonas, Manaus, 69077-000, AM, Brazil
- Laboratory of Virology and Immunology, National Institute of Amazonian Research (INPA), Manaus, 69067- 375, AM, Brazil
| | - Serge L Bogza
- Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Academician Kukhar str. 5, Kyiv, 02094, Ukraine
| | - Nathalie Bohdan
- Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Academician Kukhar str. 5, Kyiv, 02094, Ukraine
| | - Alexander B Rozhenko
- Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Academician Kukhar str. 5, Kyiv, 02094, Ukraine
- National Technical University of Ukraine 'Igor Sikorsky Kyiv Polytechnic Institute', Beresteiskyi prosp. 37, Kyiv, 03056, Ukraine
| | - Alice de Freitas Gomes
- Post-Graduate Program in Hematology, Foundation of Hematology and Hemotherapy of Amazonas, The State University of Amazon, Manaus, 69050-010, AM, Brazil
| | - Regiane Costa de Oliveira
- Post-Graduate Program in Basic and Applied Immunology, Institute of Biological Science, Federal University of Amazonas, Manaus, 69077-000, AM, Brazil
| | - Renata Galvão de Azevedo
- Post-Graduate Program in Basic and Applied Immunology, Institute of Biological Science, Federal University of Amazonas, Manaus, 69077-000, AM, Brazil
| | - Larissa Raquel Silva Maciel
- Laboratory of Virology and Immunology, National Institute of Amazonian Research (INPA), Manaus, 69067- 375, AM, Brazil
| | - Anamika Dhyani
- Post-Graduate Program in Hematology, Foundation of Hematology and Hemotherapy of Amazonas, The State University of Amazon, Manaus, 69050-010, AM, Brazil
| | - Andriy Grafov
- Materials Chemistry Division, Department of Chemistry, University of Helsinki, A.I. Virtasen aukio 1, Helsinki, 00560, Finland
| | - Gemilson Soares Pontes
- Post-Graduate Program in Basic and Applied Immunology, Institute of Biological Science, Federal University of Amazonas, Manaus, 69077-000, AM, Brazil.
- Laboratory of Virology and Immunology, National Institute of Amazonian Research (INPA), Manaus, 69067- 375, AM, Brazil.
- Post-Graduate Program in Hematology, Foundation of Hematology and Hemotherapy of Amazonas, The State University of Amazon, Manaus, 69050-010, AM, Brazil.
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11
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Luo M, Miao YR, Ke YJ, Guo AY, Zhang Q. A comprehensive landscape of transcription profiles and data resources for human leukemia. Blood Adv 2023; 7:3435-3449. [PMID: 36595475 PMCID: PMC10362280 DOI: 10.1182/bloodadvances.2022008410] [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: 06/27/2022] [Revised: 12/13/2022] [Accepted: 12/15/2022] [Indexed: 01/04/2023] Open
Abstract
As a heterogeneous group of hematologic malignancies, leukemia has been widely studied at the transcriptome level. However, a comprehensive transcriptomic landscape and resources for different leukemia subtypes are lacking. Thus, in this study, we integrated the RNA sequencing data sets of >3000 samples from 14 leukemia subtypes and 53 related cell lines via a unified analysis pipeline. We depicted the corresponding transcriptomic landscape and developed a user-friendly data portal LeukemiaDB. LeukemiaDB was designed with 5 main modules: protein-coding gene, long noncoding RNA (lncRNA), circular RNA, alternative splicing, and fusion gene modules. In LeukemiaDB, users can search and browse the expression level, regulatory modules, and molecular information across leukemia subtypes or cell lines. In addition, a comprehensive analysis of data in LeukemiaDB demonstrates that (1) different leukemia subtypes or cell lines have similar expression distribution of the protein-coding gene and lncRNA; (2) some alternative splicing events are shared among nearly all leukemia subtypes, for example, MYL6 in A3SS, MYB in A5SS, HMBS in retained intron, GTPBP10 in mutually exclusive exons, and POLL in skipped exon; (3) some leukemia-specific protein-coding genes, for example, ABCA6, ARHGAP44, WNT3, and BLACE, and fusion genes, for example, BCR-ABL1 and KMT2A-AFF1 are involved in leukemogenesis; (4) some highly correlated regulatory modules were also identified in different leukemia subtypes, for example, the HOXA9 module in acute myeloid leukemia and the NOTCH1 module in T-cell acute lymphoblastic leukemia. In summary, the developed LeukemiaDB provides valuable insights into oncogenesis and progression of leukemia and, to the best of our knowledge, is the most comprehensive transcriptome resource of human leukemia available to the research community.
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Affiliation(s)
- Mei Luo
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Center for Artificial Intelligence Biology, Hubei Bioinformatics & Molecular Imaging Key Laboratory, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
| | - Ya-Ru Miao
- Center for Artificial Intelligence Biology, Hubei Bioinformatics & Molecular Imaging Key Laboratory, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ya-Juan Ke
- Dian Diagnostics Group Co, Ltd, Hangzhou, China
- Key Laboratory of Digital Technology in Medical Diagnostics of Zhejiang Province, Hangzhou, China
| | - An-Yuan Guo
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
- Center for Artificial Intelligence Biology, Hubei Bioinformatics & Molecular Imaging Key Laboratory, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Qiong Zhang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
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12
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Iezza M, Cortesi S, Ottaviani E, Mancini M, Venturi C, Monaldi C, De Santis S, Testoni N, Soverini S, Rosti G, Cavo M, Castagnetti F. Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights. Cells 2023; 12:1703. [PMID: 37443737 PMCID: PMC10341256 DOI: 10.3390/cells12131703] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/17/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
The introduction of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of chronic myeloid leukemia (CML), leading to a dramatic improvement of the outcome of CML patients, who now have a nearly normal life expectancy and, in some selected cases, the possibility of aiming for the more ambitious goal of treatment-free remission (TFR). However, the minority of patients who fail treatment and progress from chronic phase (CP) to accelerated phase (AP) and blast phase (BP) still have a relatively poor prognosis. The identification of predictive elements enabling a prompt recognition of patients at higher risk of progression still remains among the priorities in the field of CML management. Currently, the baseline risk is assessed using simple clinical and hematologic parameters, other than evaluating the presence of additional chromosomal abnormalities (ACAs), especially those at "high-risk". Beyond the onset, a re-evaluation of the risk status is mandatory, monitoring the response to TKI treatment. Moreover, novel critical insights are emerging into the role of genomic factors, present at diagnosis or evolving on therapy. This review presents the current knowledge regarding prognostic factors in CML and their potential role for an improved risk classification and a subsequent enhancement of therapeutic decisions and disease management.
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Affiliation(s)
- Miriam Iezza
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Università di Bologna, 40138 Bologna, Italy; (S.C.); (C.M.); (S.D.S.); (N.T.); (S.S.); (M.C.); (F.C.)
| | - Sofia Cortesi
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Università di Bologna, 40138 Bologna, Italy; (S.C.); (C.M.); (S.D.S.); (N.T.); (S.S.); (M.C.); (F.C.)
| | - Emanuela Ottaviani
- Istituto di Ematologia “Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (E.O.); (M.M.); (C.V.)
| | - Manuela Mancini
- Istituto di Ematologia “Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (E.O.); (M.M.); (C.V.)
| | - Claudia Venturi
- Istituto di Ematologia “Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (E.O.); (M.M.); (C.V.)
| | - Cecilia Monaldi
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Università di Bologna, 40138 Bologna, Italy; (S.C.); (C.M.); (S.D.S.); (N.T.); (S.S.); (M.C.); (F.C.)
| | - Sara De Santis
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Università di Bologna, 40138 Bologna, Italy; (S.C.); (C.M.); (S.D.S.); (N.T.); (S.S.); (M.C.); (F.C.)
| | - Nicoletta Testoni
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Università di Bologna, 40138 Bologna, Italy; (S.C.); (C.M.); (S.D.S.); (N.T.); (S.S.); (M.C.); (F.C.)
- Istituto di Ematologia “Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (E.O.); (M.M.); (C.V.)
| | - Simona Soverini
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Università di Bologna, 40138 Bologna, Italy; (S.C.); (C.M.); (S.D.S.); (N.T.); (S.S.); (M.C.); (F.C.)
| | - Gianantonio Rosti
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS “Dino Amadori”, 47014 Meldola, Italy;
| | - Michele Cavo
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Università di Bologna, 40138 Bologna, Italy; (S.C.); (C.M.); (S.D.S.); (N.T.); (S.S.); (M.C.); (F.C.)
- Istituto di Ematologia “Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (E.O.); (M.M.); (C.V.)
| | - Fausto Castagnetti
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Università di Bologna, 40138 Bologna, Italy; (S.C.); (C.M.); (S.D.S.); (N.T.); (S.S.); (M.C.); (F.C.)
- Istituto di Ematologia “Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (E.O.); (M.M.); (C.V.)
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13
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de Castro Alves CE, Koidan G, Hurieva AN, de Freitas Gomes A, Costa de Oliveira R, Guimarães Costa A, Ribeiro Boechat AL, Correa de Oliveira A, Zahorulko S, Kostyuk A, Soares Pontes G. Cytotoxic and immunomodulatory potential of a novel [2-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-3-yl)pyridine] in myeloid leukemia. Biomed Pharmacother 2023; 162:114701. [PMID: 37062222 DOI: 10.1016/j.biopha.2023.114701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/31/2023] [Accepted: 04/10/2023] [Indexed: 04/18/2023] Open
Abstract
Cancer ranks among the leading causes of mortality worldwide. However, the efficacy of commercially available anticancer drugs is compromised by the emerging challenge of drug resistance. This study aimed to investigate the anticancer and immunomodulatory potential of a recently developed a novel [2-(4-(2,5-dimethyl-1 H-pyrrol-1-yl)- 1 H-pyrazol-3-yl) pyridine]. The cytotoxic potential of the compound was assessed using the MTT assay on both cancerous HL60 (acute myeloid leukemia) and K562 (chronic myeloid leukemia) cell lines, as well as non-cancerous Vero cells and human peripheral blood mononuclear cells (PBMCs). A clonogenic assay was employed to evaluate the anticancer efficacy of the compound, while flow cytometry was utilized to investigate its effect on cell cycle arrest. Furthermore, the immunomodulatory potential of the compound was assessed by quantifying inflammatory and anti-inflammatory biomarkers in the supernatant of PBMCs previously treated with the compound. Our study revealed that the novel pyridine ensemble exhibits selective cytotoxicity against HL60 (IC50 = 25.93 µg/mL) and K562 (IC50 = 10.42 µg/mL) cell lines, while displaying no significant cytotoxic effect on non-cancerous cells. In addition, the compound induced a decrease of 18% and 19% in the overall activity of COX-1 and COX-2, respectively. Concurrently, it upregulated the expression of cytokines including IL4, IL6, IL10, and IL12/23p40, while downregulating INFγ expression. These findings suggest that the compound has the potential to serve as a promising candidate for the treatment of acute and chronic myeloid leukemias due to its effective antiproliferative and immunomodulatory activities, without causing cytotoxicity in non-cancerous cells.
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Affiliation(s)
- Carlos Eduardo de Castro Alves
- Post-Graduate Program in Basic and Applied Immunology, Institute of Biological Science, Federal University of Amazonas, Manaus 69077-000, AM, Brazil; Laboratory of Virology and Immunology, National Institute of Amazonian Research (INPA), Manaus 69067-375, AM, Brazil
| | - Georgyi Koidan
- Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, 02660 Kyiv 94, Ukraine
| | - Anastasiia N Hurieva
- Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, 02660 Kyiv 94, Ukraine
| | - Alice de Freitas Gomes
- Laboratory of Virology and Immunology, National Institute of Amazonian Research (INPA), Manaus 69067-375, AM, Brazil; Post-Graduate Program in Hematology, The State University of Amazon, Foundation of Hematology and Hemotherapy of Amazonas, Manaus 69050-010, AM, Brazil
| | - Regiane Costa de Oliveira
- Post-Graduate Program in Basic and Applied Immunology, Institute of Biological Science, Federal University of Amazonas, Manaus 69077-000, AM, Brazil; Post-Graduate Program in Hematology, The State University of Amazon, Foundation of Hematology and Hemotherapy of Amazonas, Manaus 69050-010, AM, Brazil
| | - Allyson Guimarães Costa
- Post-Graduate Program in Basic and Applied Immunology, Institute of Biological Science, Federal University of Amazonas, Manaus 69077-000, AM, Brazil; Post-Graduate Program in Hematology, The State University of Amazon, Foundation of Hematology and Hemotherapy of Amazonas, Manaus 69050-010, AM, Brazil
| | - Antônio Luiz Ribeiro Boechat
- Post-Graduate Program in Basic and Applied Immunology, Institute of Biological Science, Federal University of Amazonas, Manaus 69077-000, AM, Brazil
| | - André Correa de Oliveira
- Laboratory of Virology and Immunology, National Institute of Amazonian Research (INPA), Manaus 69067-375, AM, Brazil
| | - Serhii Zahorulko
- Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, 02660 Kyiv 94, Ukraine
| | - Aleksandr Kostyuk
- Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, 02660 Kyiv 94, Ukraine
| | - Gemilson Soares Pontes
- Post-Graduate Program in Basic and Applied Immunology, Institute of Biological Science, Federal University of Amazonas, Manaus 69077-000, AM, Brazil; Laboratory of Virology and Immunology, National Institute of Amazonian Research (INPA), Manaus 69067-375, AM, Brazil; Post-Graduate Program in Hematology, The State University of Amazon, Foundation of Hematology and Hemotherapy of Amazonas, Manaus 69050-010, AM, Brazil.
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Fang Y, Wang YZ, Wei X, Li SM, Chen L. Infant-Type Hemispheric Glioma in a Chinese Girl: A Newly Defined Entity. Fetal Pediatr Pathol 2023; 42:114-122. [PMID: 35404193 DOI: 10.1080/15513815.2022.2061659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Infant-type hemispheric glioma is a newly defined entity in the updated 2021 WHO classification of tumors of the central nervous system. This lesion occurs in the cerebral hemispheres of newborns and infants and harbors molecular alterations in the NTRK family, ALK, ROS, or MET. Case report: A four-month-old female infant presented with a large space occupying lesion of the left cerebral hemisphere, whose histological manifestation was high-grade hemispheric infantile glioma. Tumor expressed panTRK, indicative of rearranged NTRK1, which was validated by next generation sequencing (NGS) as TPM3-NTRK1 fusion. There was homozygous deletion of CDKN2A/B, and there were ROS1, TLX3, FAT1, ABL1, MSH2, and PALB2 mutations. Conclusion: The additional genetic alterations in this case may expand the genotypic spectrum of this distinct cohort.
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Affiliation(s)
- Yuan Fang
- Department of Pathology, Anhui Provincial Children's Hospital, Hefei, China
| | - Yi-Zhen Wang
- Department of Pathology, Anhui Provincial Children's Hospital, Hefei, China
| | - Xia Wei
- Department of Pathology, Anhui Provincial Children's Hospital, Hefei, China
| | - Shao-Mei Li
- Department of Pathology, Anhui Provincial Children's Hospital, Hefei, China
| | - Lian Chen
- Department of Pathology, Children's Hospital of Fudan University, Shanghai, China
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15
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Sun H, Yan Z, Zhang S. Three atypical BCR/ABL transcripts detected simultaneously in a Philadelphia-positive acute lymphoblastic leukemia patient showing resistance to tyrosine kinase inhibitors. Int J Hematol 2023; 117:134-136. [PMID: 36087225 DOI: 10.1007/s12185-022-03451-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 08/27/2022] [Accepted: 08/29/2022] [Indexed: 01/07/2023]
Abstract
The Philadelphia (Ph) chromosome with a BCR/ABL fusion gene is a characteristic feature of chronic myeloid leukemia (CML) and partial acute lymphoblastic leukemia (ALL) patients, with different breakpoints of the BCR and ABL genes. Here, we report the case of a Ph-positive ALL patient with poor prognosis in whom simultaneous different BCR/ABL transcripts named e1a3, e1a4, and e1a5 were detected by RNA-seq analysis but not traditional RT-PCR. To our knowledge, this is the first report to describe coexistence of different atypical BCR-ABL transcripts in the same patient and that traditional TKI therapy may not overcome the poor prognosis. This finding will bring new challenges in diagnosis and monitoring for minimal residual disease.
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Affiliation(s)
- Haimin Sun
- Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Ruijin Road II 197, Shanghai, China
| | - Zeying Yan
- Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Ruijin Road II 197, Shanghai, China
| | - Sujiang Zhang
- Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Ruijin Road II 197, Shanghai, China. .,State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Ruijin Road II 197, Shanghai, China.
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16
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Salmon M, White HE, Zizkova H, Gottschalk A, Motlova E, Cerveira N, Colomer D, Coriu D, Franke GN, Gottardi E, Izzo B, Jurcek T, Lion T, Schäfer V, Venturi C, Vigneri P, Zawada M, Zuna J, Hovorkova L, Koblihova J, Klamova H, Markova MS, Srbova D, Benesova A, Polivkova V, Zackova D, Mayer J, Roeder I, Glauche I, Ernst T, Hochhaus A, Polakova KM, Cross NCP. Impact of BCR::ABL1 transcript type on RT-qPCR amplification performance and molecular response to therapy. Leukemia 2022; 36:1879-1886. [PMID: 35676453 PMCID: PMC9252903 DOI: 10.1038/s41375-022-01612-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/16/2022] [Accepted: 05/20/2022] [Indexed: 12/03/2022]
Abstract
Several studies have reported that chronic myeloid leukaemia (CML) patients expressing e14a2 BCR::ABL1 have a faster molecular response to therapy compared to patients expressing e13a2. To explore the reason for this difference we undertook a detailed technical comparison of the commonly used Europe Against Cancer (EAC) BCR::ABL1 reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) assay in European Treatment and Outcome Study (EUTOS) reference laboratories (n = 10). We found the amplification ratio of the e13a2 amplicon was 38% greater than e14a2 (p = 0.015), and the amplification efficiency was 2% greater (P = 0.17). This subtle difference led to measurable transcript-type dependent variation in estimates of residual disease which could be corrected by (i) taking the qPCR amplification efficiency into account, (ii) using alternative RT-qPCR approaches or (iii) droplet digital PCR (ddPCR), a technique which is relatively insensitive to differences in amplification kinetics. In CML patients, higher levels of BCR::ABL1/GUSB were identified at diagnosis for patients expressing e13a2 (n = 67) compared to e14a2 (n = 78) when analysed by RT-qPCR (P = 0.0005) but not ddPCR (P = 0.5). These data indicate that widely used RT-qPCR assays result in subtly different estimates of disease depending on BCR::ABL1 transcript type; these differences are small but may need to be considered for optimal patient management.
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Affiliation(s)
- Matthew Salmon
- Faculty of Medicine, University of Southampton, Southampton, UK.,Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK
| | - Helen E White
- Faculty of Medicine, University of Southampton, Southampton, UK.,Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK
| | - Hana Zizkova
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Andrea Gottschalk
- Institute for Medical Informatics and Biometry (IMB), Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Eliska Motlova
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Nuno Cerveira
- Portuguese Oncology Institute of Porto, Porto, Portugal
| | - Dolors Colomer
- Pathology Department, Hospital Clinic, Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain
| | - Daniel Coriu
- Fundeni Clinical Institute, Hematology Department, Bucharest, Romania.,Hematology Department, Faculty of Medicine, University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania
| | - Georg N Franke
- University of Leipzig Medical Center, Department for Hematology, Cellular Therapies and Hemostaseology, Leipzig, Germany
| | - Enrico Gottardi
- Laboratory of Chemical and Clinical Analysis "Area 3" A.O.U San Luigi Gonzaga-Orbassano, Turin, Italy
| | - Barbara Izzo
- Department of Molecular Medicine and Medical Biotechnology University 'Federico II' and CEINGE - Advanced Biotechnologies, Naples, Italy
| | - Tomas Jurcek
- Center of Molecular Biology and Gene Therapy, Internal Hematology and Oncology Clinic, Faculty Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Thomas Lion
- Labdia Labordiagnostik / St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria
| | - Vivien Schäfer
- Abteilung Hämatologie/Onkologie, Klinik für Innere Medizin II, University of Jena, Jena, Germany
| | - Claudia Venturi
- IRCSS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
| | - Paolo Vigneri
- University of Catania, Department of Clinical and Experimental Medicine, Center of Experimental Oncology and Hematology, Catania, Italy
| | | | - Jan Zuna
- CLIP, Dept. of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Lenka Hovorkova
- CLIP, Dept. of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Jitka Koblihova
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Hana Klamova
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | | | - Dana Srbova
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Adela Benesova
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Vaclava Polivkova
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Daniela Zackova
- Internal Hematology and Oncology Clinic, Faculty Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Jiri Mayer
- Internal Hematology and Oncology Clinic, Faculty Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Ingo Roeder
- Institute for Medical Informatics and Biometry (IMB), Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden, Germany.,National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
| | - Ingmar Glauche
- Institute for Medical Informatics and Biometry (IMB), Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Thomas Ernst
- Abteilung Hämatologie/Onkologie, Klinik für Innere Medizin II, University of Jena, Jena, Germany
| | - Andreas Hochhaus
- Abteilung Hämatologie/Onkologie, Klinik für Innere Medizin II, University of Jena, Jena, Germany
| | | | - Nicholas C P Cross
- Faculty of Medicine, University of Southampton, Southampton, UK. .,Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK.
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17
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Baccarani M, Bonifazi F, Soverini S, Castagnetti F, Gugliotta G, Saber W, Estrada-Merly N, Rosti G, Gale RP. Questions concerning tyrosine kinase-inhibitor therapy and transplants in chronic phase chronic myeloid leukaemia. Leukemia 2022; 36:1227-1236. [PMID: 35338251 PMCID: PMC9061294 DOI: 10.1038/s41375-022-01522-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 01/25/2022] [Accepted: 02/02/2022] [Indexed: 01/07/2023]
Abstract
In this provocative commentary, we consider several questions posed by the late chronic myeloid leukaemia (CML) expert Prof. Michele Baccarani, which he challenged us to address after his death. He noted only a small proportion of people with chronic phase CML receiving tyrosine kinase-inhibitor (TKI)-therapy are likely to achieve sustained therapy-free remission (TFR) and even fewer are likely to be cured. Persons most likely to fail TKItherapy can be identified at diagnosis or soon after starting TKI-therapy. These persons are likely to need lifetime TKI-therapy with attendant risks of adverse events, cost and psychological consequences. Allogeneic transplants achieve much higher rates of leukaemia-free survival compared with TKI-therapy but are associated with transplant-related adverse events including an almost 20 percent risk of transplant-related deaths within 1 year post-transplant and a compromised quality-of-life because of complications such as chronic graft-versus-host disease. Subject-, disease- and transplant-related co-variates associated with transplant outcomes are known with reasonable accuracy. Not everyone likely to fail TKI-therapy is a transplant candidate. However, in those who candidates are physicians and patients need to weigh benefits and risks of TKI-therapy versus a transplant. We suggest transplants should be more often considered in the metric when counseling people with chronic phase CML unlikely to achieve TFR with TKI-therapy. We question whether we are discounting a possible important therapy intervention; we think so.
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Affiliation(s)
- Michele Baccarani
- IRCCS Azienda Ospedaliero -Universitaria di Bologna, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Hematology 'Lorenzo e Ariosto Seràgnoli', University of Bologna, Bologna, Italy
| | | | - Simona Soverini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Hematology 'Lorenzo e Ariosto Seràgnoli', University of Bologna, Bologna, Italy
| | - Fausto Castagnetti
- IRCCS Azienda Ospedaliero -Universitaria di Bologna, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Hematology 'Lorenzo e Ariosto Seràgnoli', University of Bologna, Bologna, Italy
| | | | - Wael Saber
- Center for International Blood and Marrow Transplant Research), Milwaukee, WI, USA
- Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Noel Estrada-Merly
- Center for International Blood and Marrow Transplant Research), Milwaukee, WI, USA
| | | | - Robert Peter Gale
- Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK
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18
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Chen K, Ruan Y, Tian K, Xiong P, Xia N, Li J, Huang W, Cao F, Chen Q. Impact of BCR-ABL1 Transcript Type on Outcome in Chronic Myeloid Leukemia Patients Treated With Tyrosine Kinase Inhibitors: A Pairwise and Bayesian Network Meta-Analysis. Front Oncol 2022; 12:841546. [PMID: 35223524 PMCID: PMC8867088 DOI: 10.3389/fonc.2022.841546] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/14/2022] [Indexed: 11/13/2022] Open
Abstract
PURPOSE To evaluate the impact of BCR-ABL1 transcript type on outcome in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). METHODS PubMed, Embase and Cochrane library were systematically searched for relevant studies. Outcomes assessed were: major molecular response (MMR) at 6, 12, 18 and 60 months, deep molecular response (DMR) at 6, 12, 18 and 60 months, event-free survival (EFS), progression-free survival (PFS), overall survival (OS) and treatment-free remission (TFR). Odds ratios (ORs) and hazard ratios (HRs) were estimated and pooled using a random effect model. RESULTS A total of 16 retrospective cohort studies involving 5,411 patients were included in this study. Compared with e13a2 transcripts, there was a statistically significant advantage for patients with e14a2 (alone or with co-expressed e13a2) in terms of MMR and DMR at 6, 12 and 18 months. This benefit was sustained up to 5 years for patients with e14a2 transcripts (OR 1.60, 1.23-2.07 and 2.21, 1.71-2.87, respectively), but not for patients with both transcripts. The expression of e14a2 also improved EFS (HR 0.71, 0.53-0.94) and OS (HR 0.76, 0.57-1.00) throughout treatment period. Importantly, having e14a2 transcripts were associated with a higher rate of TFR (OR 2.94, 1.70-5.08) in CML patients attempting TKI discontinuation. Bayesian network meta-analysis showed that e14a2 had the highest probability to be the most favorable transcript type for all outcomes, followed by both and e13a2. CONCLUSIONS The expression of e14a2 had a positive impact on MMR, DMR, EFS, OS and TFR. We suggest that in the future, the e14a2 transcript can be added to the list of prognostic factors to guide clinical decisions in treating CML. SYSTEMATIC REVIEW REGISTRATION [https://www.crd.york.ac.uk/PROSPERO/#myprospero], identifier PROSPERO (CRD42021288440).
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Affiliation(s)
- Kangkang Chen
- Department of Non-communicable Diseases Control and Prevention, Shaoxing Center for Disease Control and Prevention, Shaoxing, China
| | - Yingying Ruan
- Department of General Practice, Shaoxing People's Hospital, Shaoxing, China
| | - Kewei Tian
- School of Public Health, Hangzhou Medical College, Hangzhou, China
| | - Peisheng Xiong
- Immunization Program Section, Zhanggong District Center for Disease Control and Prevention, Ganzhou, China
| | - Nan Xia
- The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Jin Li
- Department of Non-communicable Diseases Control and Prevention, Shaoxing Center for Disease Control and Prevention, Shaoxing, China
| | - Wen Huang
- Department of Non-communicable Diseases Control and Prevention, Shaoxing Center for Disease Control and Prevention, Shaoxing, China
| | - Feiyan Cao
- Emergency Department, Shaoxing Hospital of Traditional Chinese Medicine, Shaoxing, China
| | - Qifeng Chen
- Department of Non-communicable Diseases Control and Prevention, Shaoxing Center for Disease Control and Prevention, Shaoxing, China
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19
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Ismail MA, Nasrallah GK, Monne M, AlSayab A, Yassin MA, Varadharaj G, Younes S, Sorio C, Cook R, Modjtahedi H, Al-Dewik NI. Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase Inhibitors. Gene 2021; 813:146101. [PMID: 34906644 DOI: 10.1016/j.gene.2021.146101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/07/2021] [Accepted: 11/16/2021] [Indexed: 12/25/2022]
Abstract
Tyrosine kinase inhibitors (TKIs) have remarkably transformed Ph+ chronic myeloid leukemia (CML) management; however, TKI resistance remains a major clinical challenge. Mutations in BCR-ABL1 are well studied but fail to explain 20-40% of resistant cases, suggesting the activation of alternative, BCR-ABL1-independent pathways. Protein Tyrosine Phosphatase Receptor Gamma (PTPRG), a tumor suppressor, was found to be well expressed in CML patients responsive to TKIs and down-regulated in resistant patients. In this study, we aimed to identify genetic variants in PTPRG that could potentially modulate TKIs response in CML patients. DNA was extracted from peripheral blood samples collected from two CML cohorts (Qatar and Italy) and targeted exome sequencing was performed. Among 31 CML patients, six were TKI-responders and 25 were TKI-resistant. Sequencing identified ten variants, seven were annotated and three were novel SNPs (c.1602_1603insC, c.85+86delC, and c.2289-129delA). Among them, five variants were identified in 15 resistant cases. Of these, one novel exon variant (c.1602_1603insC), c.841-29C>T (rs199917960) and c.1378-224A>G (rs2063204) were found to be significantly different between the resistant cases compared to responders. Our findings suggest that PTPRG variants may act as an indirect resistance mechanism of BCR-ABL1 to affect TKI treatment.
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Affiliation(s)
- Mohamed A Ismail
- School of Life Science, Pharmacy and Chemistry, Faculty of science, engineering & computing-Kingston University London, United Kingdom; Interim Translational Research Institute (iTRI), Hamad Medical Corporation (HMC), Doha, Qatar
| | - Gheyath K Nasrallah
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, Doha, Qatar
| | - Maria Monne
- Centro di Diagnostica Biomolecolare e Citogenetica Emato-Oncologica, "San Francesco" Hospital, Nuoro, Italy
| | - Ali AlSayab
- Interim Translational Research Institute (iTRI), Hamad Medical Corporation (HMC), Doha, Qatar
| | - Mohamed A Yassin
- Department of Medical Oncology, National Centre for Cancer Care and Research, Hamad Medical Corporation (HMC), Doha, Qatar
| | | | - Salma Younes
- Department of Research, Women's Wellness and Research Center, Hamad Medical Corporation, Qatar
| | - Claudio Sorio
- Department of Medicine, University of Verona, Verona, Italy
| | - Richard Cook
- School of Life Science, Pharmacy and Chemistry, Faculty of science, engineering & computing-Kingston University London, United Kingdom
| | - Helmout Modjtahedi
- School of Life Science, Pharmacy and Chemistry, Faculty of science, engineering & computing-Kingston University London, United Kingdom
| | - Nader I Al-Dewik
- Interim Translational Research Institute (iTRI), Hamad Medical Corporation (HMC), Doha, Qatar; Faculty of Health and Social Care Sciences, Kingston University, St. George's University of London, UK; Clinical and Metabolic Genetics, Department of Pediatrics, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar; College of Health and Life Science (CHLS), Hamad Bin Khalifa University (HBKU), Doha, Qatar.
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Abstract
Purpose of Review Treatment-free remission (TFR) is considered one of the main goals of therapy in patients with CML. Our goal in this paper is to review the current data on TFR, and discuss future directions. Recent Findings Multiple studies have demonstrated that attempting a treatment-free remission is safe and effective in a select group of patients. More recent data suggested that undetectable BCR-ABL1 by digital PCR prior to discontinuation is highly predictive of successful TFR. However, some patients have a successful TFR with no evidence of clinical disease despite persistent detectable BCR-ABL1. Some recent studies have shed some more light on possible mechanisms for this phenomena. Some possible mechanisms include immune mechanism, BCR-ABL1 detected in the lymphoid component only, or stem cell exhaustion. Summary TFR should be discussed with patients with CML. Patients who achieve a sustained deep molecular response may be eligible to attempt TFR, however, setting expectations that overall only 20% of patients with newly diagnosed CML will achieve a successful TFR. The importance of compliance to treatment early on cannot be overemphasized. Further studies using other drugs to get patients to a deeper remission in order to be eligible for TFR attempt, or attempting a second TFR in patients who had disease recurrence after first TFR attempt, are currently underway.
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21
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Karasu N, Akalin H, Gokce N, Yildirim A, Demir M, Kulak H, Celik S, Keklik M, Dundar M. Detection of mutations in CML patients resistant to tyrosine kinase inhibitor: imatinib mesylate therapy. Med Oncol 2021; 38:120. [PMID: 34453624 DOI: 10.1007/s12032-021-01571-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 08/17/2021] [Indexed: 11/28/2022]
Abstract
Imatinib mesylate, a tyrosine kinase inhibitor, is the first choice in chronic myeloid leukemia treatment. However, resistance to imatinib may develop with time and in some cases, patients may not respond at all to imatinib. Progressive resistance to imatinib therapy is often due to mutations in the BCR/ABL region. Within the scope of our study 124 patients were evaluated via pyrosequencing between 2015 and 2020. In this regard, 32 patients who have a partial response and have no response to imatinib therapy were included in the study. In addition, next-generation sequencing (NGS) analysis was performed on 15 patients who were resistant to imatinib treatment according to the molecular follow-up reports. With pyrosequencing, 5 cases out of a total of 124 were found to be positive. This means that approximately 4.03% of the proportion is positive. But when we examined only 32 patients who have a partial response and have no response to imatinib therapy this rate is rising 15.6%. NGS analysis was performed with 15 patients who have no mutation with pyrosequencing of 32 patients and VUS (Variant of Uncertain Significance) mutation was detected in one. In this study, our aim was to determine the mutations of the BCR/ABL and to evaluate the mutations by NGS and pyrosequencing. Our study is important in terms of comparing the pyrosequencing with NGS mutation rates, drawing attention to the clinical importance of log reduction.
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Affiliation(s)
- Nilgun Karasu
- Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Hilal Akalin
- Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Nuriye Gokce
- Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Abdulbaki Yildirim
- Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Mikail Demir
- Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Hande Kulak
- Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Serhat Celik
- Department of Hematology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Muzaffer Keklik
- Department of Hematology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Munis Dundar
- Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
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22
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Gou X, Xu L, Yang S, Cheng X, Wu H, Zhang D, Shi W, Ding S, Zhang Y, Cheng W. One-Pot Identification of BCR/ABL p210 Transcript Isoforms Based on Nanocluster Beacon. ACS Sens 2021; 6:2928-2937. [PMID: 34324312 DOI: 10.1021/acssensors.1c00695] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The BCR/ABLp210 fusion gene is a classic biomarker of chronic myeloid leukemia, which can be divided into e13a2 and e14a2 isoforms according to different breakpoints. These two isoforms showed distinct differences in clinical manifestation, treatment effect, and prognosis risk. Herein, a strategy based on nanocluster beacon (NCB) fluorescence was developed to identify the e13a2 and e14a2 isoforms in one-pot. Because the fluorescence of AgNCs can be activated when they are placed in proximity to the corresponding enhancer sequences, thymine-rich (T-rich) or guanine-rich (G-rich). In this work, we explored an ideal DNA-AgNCs template as an excellent molecular reporter with a high signal-to-noise ratio. After recognition with the corresponding isoforms, the AgNCs can be pulled closer to the T-rich or G-rich sequences to form a three-way junction structure and generate fluorescence with corresponding wavelengths. Therefore, by distinguishing the corresponding wavelengths of AgNCs, we successfully identified two isoforms in one tube with the limitation of 16 pM for e13a2 and 9 pM for e14a2. Moreover, this strategy also realized isoform identification in leukemia cells and newly diagnosed CML patients within 40 min, which provides a powerful tool to distinguish fusion gene subtypes at the same time.
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Affiliation(s)
- Xiaolong Gou
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Lulu Xu
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- The Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Suqing Yang
- Chongqing Testing & Lnspection Center for Medical Devices, Chongqing 400016, China
| | - Xiaoxue Cheng
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Haiping Wu
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Decai Zhang
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Weicheng Shi
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Shijia Ding
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yuhong Zhang
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wei Cheng
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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Saifullah HH, Lucas CM. Treatment-Free Remission in Chronic Myeloid Leukemia: Can We Identify Prognostic Factors? Cancers (Basel) 2021; 13:cancers13164175. [PMID: 34439327 PMCID: PMC8392063 DOI: 10.3390/cancers13164175] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 08/04/2021] [Accepted: 08/08/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Chronic myeloid leukemia (CML) is a blood cancer. Unlike other cancers CML treatment is lifelong and many patients experience side effects. For those patients who respond well to treatment and achieve deep molecular remission, quality of life is impacted because of continuous treatment. In this review, we look at emerging clinical trials which aim to investigate which patients can safely stop treatment. Treatment-free remission is the ultimate goal for CML patients, but there is still a gap in our knowledge as to why some patients can achieve treatment-free remission, while others relapse when treatment is stopped. Here we discuss if there are any prognostic factors that can predict the best candidates who qualify for treatment discontinuation, with a view to keeping them in remission. Abstract Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukaemia (CML) drastically improved. With the introduction of these agents, CML is now considered a chronic disease for some patients. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKI became a goal for patients with chronic phase CML. Patients who achieved deep molecular response (DMR) and discontinued TKI, remained in treatment-free remission (TFR). Currently, the data from the published literature demonstrate that 40–60% of patients achieve TFR, with relapses occurring within the first six months. In addition, almost all patients who relapsed regained a molecular response upon retreatment, indicating TKI discontinuation is safe. However, there is still a gap in understanding the mechanisms behind TFR, and whether there are prognostic factors that can predict the best candidates who qualify for TKI discontinuation with a view to keeping them in TFR. Furthermore, the information about a second TFR attempt and the role of gradual de-escalation of TKI before complete cessation is limited. This review highlights the factors predicting success or failure of TFR. In addition, it examines the feasibility of a second TFR attempt after the failure of the first one, and the current guidelines concerning TFR in clinical practice.
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Affiliation(s)
- Hilbeen Hisham Saifullah
- Chester Medical School, University of Chester, Bache Hall, Chester CH2 1BR, UK
- Correspondence: (H.H.S.); (C.M.L.)
| | - Claire Marie Lucas
- Chester Medical School, University of Chester, Bache Hall, Chester CH2 1BR, UK
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3GA, UK
- Correspondence: (H.H.S.); (C.M.L.)
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Habib EM, Nosiar NA, Eid MA, Taha AM, Sherief DE, Hassan AE, Abdel Ghafar MT. MiR-150 Expression in Chronic Myeloid Leukemia: Relation to Imatinib Response. Lab Med 2021; 53:58-64. [PMID: 34350970 DOI: 10.1093/labmed/lmab040] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE To assess the circulating micro-RNA-150 (miR-150) expression in patients with chronic myeloid leukemia (CML) in relation to imatinib response. METHODS Sixty patients with CML and 20 age- and sex-matched control subjects were enrolled. Circulating miR-150 levels were assessed by quantitative real-time polymerase chain reaction on days 0, 14, and 90 of imatinib therapy for patients and once for control subjects. RESULTS The baseline miR-150 expression was significantly lower in patients with CML than in control subjects with subsequent elevation at 14 and 90 days after the start of imatinib treatment. Early treatment response (ETR) at 90 days was the main study outcome. The miR-150 expression had a significantly higher level in patients with CML with ETR. On multivariate analysis, miR-150 on day 14 was significantly related to ETR in patients with CML with predictive efficacy (area under the curve = 0.838, 72.9% sensitivity, and 84.2% specificity). CONCLUSION We found that miR-150 expression on day 14 of imatinib treatment is a useful early predictive candidate for imatinib response in patients with CML.
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Affiliation(s)
- Eman M Habib
- Department of Clinical Pathology, Faculty of Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
| | - Nahla A Nosiar
- Department of Clinical Pathology, Faculty of Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
| | - Manal A Eid
- Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Atef M Taha
- Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Dalia E Sherief
- Department of Clinical Pathology, Faculty of Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
| | - Asmaa E Hassan
- Department of Clinical Pathology, Faculty of Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
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Why chronic myeloid leukaemia cannot be cured by tyrosine kinase-inhibitors. Leukemia 2021; 35:2199-2204. [PMID: 34002028 DOI: 10.1038/s41375-021-01272-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 03/24/2021] [Accepted: 04/28/2021] [Indexed: 01/29/2023]
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26
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Impact of BCR-ABL1 Transcript Type on Response, Treatment-Free Remission Rate and Survival in Chronic Myeloid Leukemia Patients Treated with Imatinib. J Clin Med 2021; 10:jcm10143146. [PMID: 34300312 PMCID: PMC8307111 DOI: 10.3390/jcm10143146] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/12/2021] [Accepted: 07/13/2021] [Indexed: 12/20/2022] Open
Abstract
The most frequent BCR-ABL1-p210 transcripts in chronic myeloid leukemia (CML) are e14a2 and e13a2. Imatinib (IM) is the most common first-line tyrosine–kinase inhibitor (TKI) used to treat CML. Some studies suggest that BCR-ABL1 transcript types confer different responses to IM. The objective of this study was to correlate the expression of e14a2 or e13a2 to clinical characteristics, cumulative cytogenetic and molecular responses to IM, acquisition of deep molecular response (DMR) and its duration (sDMR), progression rate (CIP), overall survival (OS), and treatment-free remission (TFR) rate. We studied 202 CML patients, 76 expressing the e13a2 and 126 the e14a2, and correlated the differential transcript expression with the above-mentioned parameters. There were no differences in the cumulative incidence of cytogenetic responses nor in the acquisition of DMR and sDMR between the two groups, but the e14a2 transcript had a positive impact on molecular response during the first 6 months, whereas the e13a2 was associated with improved long-term OS. No correlation was observed between the transcript type and TFR rate.
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27
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Patel KD, De M, Jethva DD, Rathod BS, Patel PS. Alterations in Sialylation Patterns are Significantly Associated with Imatinib Mesylate Resistance in Chronic Myeloid Leukemia. Arch Med Res 2021; 53:51-58. [PMID: 34275666 DOI: 10.1016/j.arcmed.2021.06.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 01/24/2021] [Accepted: 06/02/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND AND AIM The study examined sialylation changes for their potential predictive value in assessment of imatinib mesylate (IM) resistance, alone and/or with BCR-ABL1 transcript variants among chronic myeloid leukemia (CML) cases. METHODS A total of 98 CML cases (un-treated cases, IM non-responders and IM responders) were enrolled in the study. Total sialic acid (TSA) and total protein (TP) levels were estimated spectrophotometrically, the expression profiles of BCR-ABL1, ST3GAL1 and ST3GAL2 were evaluated using qRT-PCR assays and BCR-ABL1 transcript variants were identified through subjecting PCR products to agarose gel electrophoresis. RESULTS The results manifested increase in e14a2 transcript and decrease in co-expression of both transcripts (e13a2 and e14a2) in IM non-responders than un-treated CML cases. Notably, TSA/TP ratio was higher, whereas ST3GAL1 and ST3GAL2 expressions were lower in un-treated CML cases and IM non-responders as against IM responders. Further, ST3GAL2 expression was lower in un-treated CML cases than IM non-responders. Receiver operating characteristic curves also proved their discriminatory efficiencies. Decisively, the rise in TSA levels and the fall in ST3GAL1 and ST3GAL2 levels were evidently related to CML progression and clinical indicators of treatment failure (high BCR-ABL1 ratio, high WBC count, high platelet count and low Hb levels). The alterations in TSA, ST3GAL1 and ST3GAL2 levels were remarkably associated with each other. CONCLUSIONS The altered levels of TSA, ST3GAL1 and ST3GAL2 are, to a significant extent, associated with IM resistance in CML, which have clinical relevance in treatment monitoring and IM resistance treatment.
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Affiliation(s)
- Kinjal D Patel
- Cancer Biology Department, The Gujarat Cancer and Research Institute, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India
| | - Maitri De
- Cancer Biology Department, The Gujarat Cancer and Research Institute, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India
| | - Disha D Jethva
- Cancer Biology Department, The Gujarat Cancer and Research Institute, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India
| | - Bharati S Rathod
- Cancer Biology Department, The Gujarat Cancer and Research Institute, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India
| | - Prabhudas S Patel
- Cancer Biology Department, The Gujarat Cancer and Research Institute, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India.
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Ismail MA, Vezzalini M, Morsi H, Abujaber A, Al Sayab A, Siveen K, Yassin MA, Monne M, Samara M, Cook R, Sorio C, Modjtahedi H, Al-Dewik NI. Predictive value of tyrosine phosphatase receptor gamma for the response to treatment tyrosine kinase inhibitors in chronic myeloid leukemia patients. Sci Rep 2021; 11:8833. [PMID: 33893334 PMCID: PMC8065106 DOI: 10.1038/s41598-021-86875-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 03/22/2021] [Indexed: 01/20/2023] Open
Abstract
Protein tyrosine phosphatase receptor gamma (PTPRG) is a member of the receptor-like family protein tyrosine phosphatases and acts as a tumor suppressor gene in different neoplasms. Recent studies reported the down-regulation of PTPRG expression levels in Chronic Myeloid Leukemia disease (CML). In addition, the BCR-ABL1 transcript level is currently a key predictive biomarker of CML response to treatment with Tyrosine Kinase Inhibitors (TKIs). The aim of this study was to employ flow cytometry to monitor the changes in the expression level of PTPRG in the white blood cells (WBCs) of CML patients at the time of diagnosis and following treatment with TKIs. WBCs from peripheral blood of 21 CML patients were extracted at diagnosis and during follow up along with seven healthy individuals. The PTPRG expression level was determined at protein and mRNA levels by both flow cytometry with monoclonal antibody (TPγ B9-2) and RT-qPCR, and BCR-ABL1 transcript by RT-qPCR, respectively. PTPRG expression was found to be lower in the neutrophils and monocytes of CML patients at time of diagnosis compared to healthy individuals. Treatment with TKIs nilotinib and Imatinib Mesylate restored the expression of PTPRG in the WBCs of CML patients to levels observed in healthy controls. Moreover, restoration levels were greatest in optimal responders and occurred earlier with nilotinib compared to imatinib. Our results support the measurement of PTPRG expression level in the WBCs of CML patients by flow cytometry as a monitoring tool for the response to treatment with TKIs in CML patients.
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MESH Headings
- Adult
- Antineoplastic Agents/therapeutic use
- Biomarkers, Tumor/metabolism
- Case-Control Studies
- Female
- Flow Cytometry
- Fusion Proteins, bcr-abl/genetics
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Lymphocytes/drug effects
- Male
- Middle Aged
- Protein Kinase Inhibitors/therapeutic use
- RNA, Messenger/genetics
- Receptor-Like Protein Tyrosine Phosphatases, Class 5/genetics
- Receptor-Like Protein Tyrosine Phosphatases, Class 5/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Treatment Outcome
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Affiliation(s)
- Mohamed A Ismail
- School of Life Science, Pharmacy and Chemistry, Faculty of Science, Engineering and Computing, Kingston University London, London, United Kingdom.
- Interim Translational Research Institute (iTRI), Hamad Medical Corporation (HMC), Doha, Qatar.
| | | | - Hisham Morsi
- Quality of Life Unit, National Center for Cancer Care and Research, (NCCCR), Hamad Medical Corporation (HMC), Doha, Qatar
| | - Ahmad Abujaber
- Interim Translational Research Institute (iTRI), Hamad Medical Corporation (HMC), Doha, Qatar
| | - Ali Al Sayab
- Interim Translational Research Institute (iTRI), Hamad Medical Corporation (HMC), Doha, Qatar
| | - Kodappully Siveen
- Interim Translational Research Institute (iTRI), Hamad Medical Corporation (HMC), Doha, Qatar
| | - Mohamed A Yassin
- Department of Medical Oncology, National Centre for Cancer Care and Research, Hamad Medical Corporation (HMC), Doha, Qatar
| | - Maria Monne
- Centro di Diagnostica Biomolecolare e Citogenetica Emato-Oncologica, "San Francesco" Hospital, Nuoro, Italy
| | - Muthanna Samara
- Department of Psychology, Kingston University London, Penrhyn Road, Kingston upon Thames, KT1 2EE, United Kingdom
| | - Richard Cook
- School of Life Science, Pharmacy and Chemistry, Faculty of Science, Engineering and Computing, Kingston University London, London, United Kingdom
| | - Claudio Sorio
- Department of Medicine, University of Verona, Verona, Italy
| | - Helmout Modjtahedi
- School of Life Science, Pharmacy and Chemistry, Faculty of Science, Engineering and Computing, Kingston University London, London, United Kingdom
| | - Nader I Al-Dewik
- School of Life Science, Pharmacy and Chemistry, Faculty of Science, Engineering and Computing, Kingston University London, London, United Kingdom.
- Qatar Medical Genetic Center (QMGC), Hamad General Hospital (HGH), and Interim Translational Research Institute (iTRI), Hamad Medical Corporation (HMC), P.O. BOX. 3050, Doha, Qatar.
- College of Health and Life Science (CHLS), Genomics and Precision Medicine, Hamad Bin Khalifa University (HBKU), Doha, Qatar.
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29
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Liu Y, Duan C, Zhang C. E3 Ubiquitin Ligase in Anticancer Drugdsla Resistance: Recent Advances and Future Potential. Front Pharmacol 2021; 12:645864. [PMID: 33935743 PMCID: PMC8082683 DOI: 10.3389/fphar.2021.645864] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 02/24/2021] [Indexed: 12/31/2022] Open
Abstract
Drug therapy is the primary treatment for patients with advanced cancer. The use of anticancer drugs will inevitably lead to drug resistance, which manifests as tumor recurrence. Overcoming chemoresistance may enable cancer patients to have better therapeutic effects. However, the mechanisms underlying drug resistance are poorly understood. E3 ubiquitin ligases (E3s) are a large class of proteins, and there are over 800 putative functional E3s. E3s play a crucial role in substrate recognition and catalyze the final step of ubiquitin transfer to specific substrate proteins. The diversity of the set of substrates contributes to the diverse functions of E3s, indicating that E3s could be desirable drug targets. The E3s MDM2, FBWX7, and SKP2 have been well studied and have shown a relationship with drug resistance. Strategies targeting E3s to combat drug resistance include interfering with their activators, degrading the E3s themselves and influencing the interaction between E3s and their substrates. Research on E3s has led to the discovery of possible therapeutic methods to overcome the challenging clinical situation imposed by drug resistance. In this article, we summarize the role of E3s in cancer drug resistance from the perspective of drug class.
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Affiliation(s)
- Yuanqi Liu
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China.,Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis & Treatment, Changsha, China
| | - Chaojun Duan
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China.,Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis & Treatment, Changsha, China.,Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Chunfang Zhang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China.,Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis & Treatment, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
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30
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Sampaio MM, Santos MLC, Marques HS, Gonçalves VLDS, Araújo GRL, Lopes LW, Apolonio JS, Silva CS, Santos LKDS, Cuzzuol BR, Guimarães QES, Santos MN, de Brito BB, da Silva FAF, Oliveira MV, Souza CL, de Melo FF. Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs: A literature review. World J Clin Oncol 2021; 12:69-94. [PMID: 33680875 PMCID: PMC7918527 DOI: 10.5306/wjco.v12.i2.69] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 12/22/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly - the presence of the Philadelphia chromosome. The advances in cytogenetic and molecular assays are of great importance to the diagnosis, prognosis, treatment, and monitoring of CML. The discovery of the breakpoint cluster region (BCR)-Abelson murine leukemia (ABL) 1 fusion oncogene has revolutionized the treatment of CML patients by allowing the development of targeted drugs that inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein. Tyrosine kinase inhibitors (known as TKIs) are the standard therapy for CML and greatly increase the survival rates, despite adverse effects and the odds of residual disease after discontinuation of treatment. As therapeutic alternatives, the subsequent TKIs lead to faster and deeper molecular remissions; however, with the emergence of resistance to these drugs, immunotherapy appears as an alternative, which may have a cure potential in these patients. Against this background, this article aims at providing an overview on CML clinical management and a summary on the main targeted drugs available in that context.
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Affiliation(s)
- Mariana Miranda Sampaio
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Maria Luísa Cordeiro Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083-900, Bahia, Brazil
| | | | - Glauber Rocha Lima Araújo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Weber Lopes
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Jonathan Santos Apolonio
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Camilo Santana Silva
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Kauany de Sá Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Beatriz Rocha Cuzzuol
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Mariana Novaes Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Márcio Vasconcelos Oliveira
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Cláudio Lima Souza
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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31
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Suttorp M, Millot F, Sembill S, Deutsch H, Metzler M. Definition, Epidemiology, Pathophysiology, and Essential Criteria for Diagnosis of Pediatric Chronic Myeloid Leukemia. Cancers (Basel) 2021; 13:cancers13040798. [PMID: 33672937 PMCID: PMC7917817 DOI: 10.3390/cancers13040798] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/04/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary The low incidence (1:1,000,000) of chronic myeloid leukemia (CML) in the first two decades of life presents an obstacle to accumulation of pediatric experience and knowledge on this leukemia. Biological features of CML are shared but also differing between adult and pediatric patients. This review aims; (i) to define the disease based on an unified terminology, (ii) to list the diseases to be considered as a differential diagnosis in children, (iii) to outlines the morphological, histopathological and immuno-phenotypical findings of pediatric CML, (iv) to illustrate rare but classical complications resulting from high white cell and platelet counts at diagnosis, and (v) to recommend a uniform approach for the diagnostic procedures to be applied. Evidently, only a clear detailed picture of all relevant features can lay the basis for standardized treatment approaches. Abstract Depending on the analytical tool applied, the hallmarks of chronic myeloid leukemia (CML) are the Philadelphia Chromosome and the resulting mRNA fusion transcript BCR-ABL1. With an incidence of 1 per 1 million of children this malignancy is very rare in the first 20 years of life. This article aims to; (i) define the disease based on the WHO nomenclature, the appropriate ICD 11 code and to unify the terminology, (ii) delineate features of epidemiology, etiology, and pathophysiology that are shared, but also differing between adult and pediatric patients with CML, (iii) give a short summary on the diseases to be considered as a differential diagnosis of pediatric CML, (iv) to describe the morphological, histopathological and immunophenotypical findings of CML in pediatric patients, (v) illustrate rare but classical complications resulting from rheological problems observed at diagnosis, (vi) list essential and desirable diagnostic criteria, which hopefully in the future will help to unify the attempts when approaching this rare pediatric malignancy.
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Affiliation(s)
- Meinolf Suttorp
- Pediatric Hemato-Oncology, Medical Faculty, Technical University Dresden, D-01307 Dresden, Germany
- Correspondence: ; Tel.: +49-351-458-3522; Fax: +49-351-458-5864
| | - Frédéric Millot
- Inserm CIC 1402, University Hospital Poitiers, F-86000 Poitiers, France; (F.M.); (H.D.)
| | - Stephanie Sembill
- Pediatric Oncology and Hematology, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, D-91504 Erlangen, Germany; (S.S.); (M.M.)
| | - Hélène Deutsch
- Inserm CIC 1402, University Hospital Poitiers, F-86000 Poitiers, France; (F.M.); (H.D.)
| | - Markus Metzler
- Pediatric Oncology and Hematology, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, D-91504 Erlangen, Germany; (S.S.); (M.M.)
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Kargbo RB. Breakthrough in Degradation of BCR-ABL Fusion Protein for the Treatment of Cancer. ACS Med Chem Lett 2020; 11:2359-2360. [PMID: 33335652 DOI: 10.1021/acsmedchemlett.0c00587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Indexed: 11/28/2022] Open
Affiliation(s)
- Robert B. Kargbo
- Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States
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33
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Atallah E, Schiffer CA. Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when and for whom? Haematologica 2020; 105:2738-2745. [PMID: 33054106 PMCID: PMC7716356 DOI: 10.3324/haematol.2019.242891] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 09/17/2020] [Indexed: 11/09/2022] Open
Abstract
Treatment discontinuation is considered one of the main goals of therapy for patients with chronic myeloid leukemia. Several criteria are felt to be necessary to consider discontinuation, while others may predict a better chance of achieving treatment-free remission. Criteria for discontinuation include patients in chronic phase chronic myeloid leukemia, a minimum duration of tyrosine kinase inhibitor therapy of 3 years, sustained deep molecular response for at least 2 years and a molecular response of at least MR4. In addition, proper education of the patient on the need for more frequent monitoring, possible side effects related to stopping and having a reliable real-time quantitative polymerase chain reaction laboratory are paramount to the safety and success of treatment-free remission. Realistically though, a maximum of only 20-30% of newly diagnosed patients will be able to achieve a successful treatment-free remission. In this article we will review for whom and when a trial of discontinuation should be considered.
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Affiliation(s)
| | - Charles A Schiffer
- Karmanos Cancer Institute, Wayne State University School of Medicine, Milwaukee, WI.
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34
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Molica M, Noguera NI, Trawinska MM, Martinelli G, Cerchione C, Abruzzese E. Treatment free remission in chronic myeloid leukemia: Lights and shadows. Hematol Rep 2020; 12:8950. [PMID: 33042501 PMCID: PMC7520857 DOI: 10.4081/hr.2020.8950] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Indexed: 01/03/2023] Open
Abstract
In addition to the best possible overall survival, discontinuation of the tyrosine kinase-inhibitor (TKI) treatment [treatment free remission (TFR)] without observing a recurrence of the disease has become a standard part of chronic myeloid leukemia (CML) care. Worldwide, more than 2000 patients with CML have attempted TFR, and very rare instances of disease transformation have been reported. Several studies in the last decade have demonstrated the feasibility and safety of TKI discontinuation in selected patients with CML who achieve deep and sustained molecular response with TKI. This has moved prime-time into clinical practice although open questions remain in terms of understanding the disease biology that leads to successful TKI cessation in some patients while not in others. Despite the remaining questions regarding which factors may be considered predictive for TFR, treatment interruption is a safe option provided that adequate molecular monitoring is available, with prompt re-initiation of TKIs as soon as major molecular response has been lost. Data from ongoing trials should help refine decisions as to which patients are the best candidates to attempt TKI discontinuation, frequency of a safe monitoring, optimal strategies to sustain ongoing TFR and increase the number of patients who can access to discontinuation programs.
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Affiliation(s)
| | - Nelida I Noguera
- Department of Biomedicine and Prevention, Tor Vergata University of Rome
| | | | - Giovanni Martinelli
- Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy
| | - Claudio Cerchione
- Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy
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Kuang Y, Han X, Cao P, Xiong D, Peng Y, Liu Z, Xu Z, Liang L, Roy M, Liu J, Nie L, Zhang J. p19 INK4d inhibits proliferation and enhances imatinib efficacy through BCR-ABL signaling pathway in chronic myeloid leukemia. Blood Cells Mol Dis 2020; 85:102477. [PMID: 32711219 DOI: 10.1016/j.bcmd.2020.102477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/08/2020] [Accepted: 07/10/2020] [Indexed: 11/28/2022]
Abstract
Chronic myeloid leukemia (CML) is a kind of myeloproliferative disorder caused by a constitutively active BCR-ABL tyrosine kinase. Tyrosine kinase inhibitors (TKIs), imatinib and its derivatives, have achieved great progress in the treatment of CML. However, many CML patients do not respond to TKIs alone. p19INK4d, a cyclin-dependent kinase inhibitor, plays important roles in proliferation, DNA damage repair, apoptosis and cell differentiation, but its role in CML is unknown. Herein, we found that the expression of p19INK4d in CML patients was significantly lower than that in healthy controls. p19INK4d overexpression inhibits cell proliferation through cell cycle arrest, and cooperates with imatinib to inhibit CML more effectively in vitro and in vivo. Mechanistically, p19INK4d decreased the expression of BCR-ABL and its downstream molecules p-Mek1/2, moreover, the expression of Gli-1, c-myc, MUC1, Shh and TC48 also reduced significantly. Collectively, p19INK4d inhibits proliferation and enhances imatinib efficacy in the treatment of CML. These findings maybe have implications for developing potential targets to increase imatinib sensitivity for CML.
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Affiliation(s)
- Yijin Kuang
- Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Xu Han
- Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Pengfei Cao
- Department of Hematology, Xiangya Hospital, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha 410008, China
| | - Dehui Xiong
- Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Yuanliang Peng
- Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
| | - Zhaoping Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of South China University, Hengyang 421000, China
| | - Zhenru Xu
- Department of Clinical Laboratory, The First Affiliated Hospital of South China University, Hengyang 421000, China
| | - Long Liang
- Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Mridul Roy
- Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Jing Liu
- Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; Erythropoiesis Research Center, Central South University, Changsha 410078, China
| | - Ling Nie
- Department of Hematology, Xiangya Hospital, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha 410008, China.
| | - Ji Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of South China University, Hengyang 421000, China.
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Ismail MA, Samara M, Al Sayab A, Alsharshani M, Yassin MA, Varadharaj G, Vezzalini M, Tomasello L, Monne M, Morsi H, Qoronfleh MW, Zayed H, Cook R, Sorio C, Modjtahedi H, Al-Dewik NI. Aberrant DNA methylation of PTPRG as one possible mechanism of its under-expression in CML patients in the State of Qatar. Mol Genet Genomic Med 2020; 8:e1319. [PMID: 32700424 PMCID: PMC7549574 DOI: 10.1002/mgg3.1319] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 02/06/2023] Open
Abstract
Background Several studies showed that aberrant DNA methylation is involved in leukemia and cancer pathogenesis. Protein tyrosine phosphatase receptor gamma (PTPRG) expression is a natural inhibitory mechanism that is downregulated in chronic myeloid leukemia (CML) disease. The mechanism behind its downregulation has not been fully elucidated yet. Aim This study aimed to investigate the CpG methylation status at the PTPRG locus in CML patients. Methods Peripheral blood samples from CML patients at time of diagnosis [no tyrosine kinase inhibitors (TKIs)] (n = 13), failure to (TKIs) treatment (n = 13) and healthy controls (n = 6) were collected. DNA was extracted and treated with bisulfite treatment, followed by PCR, sequencing of 25 CpG sites in the promoter region and 26 CpG sites in intron‐1 region of PTPRG. The bisulfite sequencing technique was employed as a high‐resolution method. Results CML groups (new diagnosed and failed treatment) showed significantly higher methylation levels in the promoter and intron‐1 regions of PTPRG compared to the healthy group. There were also significant differences in methylation levels of CpG sites in the promoter and intron‐1 regions amongst the groups. Conclusion Aberrant methylation of PTPRG is potentially one of the possible mechanisms of PTPRG downregulation detected in CML.
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Affiliation(s)
- Mohamed A Ismail
- School of Life Science, Pharmacy and Chemistry, Faculty of Science, Engineering & ComputingFaculty of Science, Engineering & Computing, Kingston University London, Kingston-Upon-Thames, UK.,Interim Translational Research Institute (iTRI), Hamad Medical Corporation (HMC), Doha, Qatar
| | - Muthanna Samara
- Department of Psychology, Kingston University London, Kingston upon Thames, London, UK
| | - Ali Al Sayab
- Interim Translational Research Institute (iTRI), Hamad Medical Corporation (HMC), Doha, Qatar
| | - Mohamed Alsharshani
- Diagnostic Genetics Division (DGD), Department of Laboratory Medicine and Pathology (DLMP), Hamad Medical Corporation (HMC), Doha, Qatar
| | - Mohamed A Yassin
- Department of Medical Oncology, National Centre for Cancer Care and Research, Hamad Medical Corporation (HMC), Doha, Qatar
| | | | - Marzia Vezzalini
- General Pathology Division, Department of Medicine, University of Verona, Verona, Italy
| | - Luisa Tomasello
- Wexner Medical Center, Biomedical Research Tower, The Ohio State University, Columbus, OH, USA
| | - Maria Monne
- Centro di Diagnostica Biomolecolare e Citogenetica Emato-Oncologica, San Francesco" Hospital, Nuoro, Italy
| | - Hisham Morsi
- Quality of Life unit, National Center for Cancer Care and Research, (NCCCR), Hamad Medical Corporation (HMC), Doha, Qatar
| | - M Walid Qoronfleh
- World Innovation Summit for Healthcare (WISH), Qatar Foundation, Doha, Qatar
| | - Hatem Zayed
- Department of Biomedical Sciences, Biomedical Research Center, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Richard Cook
- School of Life Science, Pharmacy and Chemistry, Faculty of Science, Engineering & ComputingFaculty of Science, Engineering & Computing, Kingston University London, Kingston-Upon-Thames, UK
| | - Claudio Sorio
- General Pathology Division, Department of Medicine, University of Verona, Verona, Italy
| | - Helmout Modjtahedi
- School of Life Science, Pharmacy and Chemistry, Faculty of Science, Engineering & ComputingFaculty of Science, Engineering & Computing, Kingston University London, Kingston-Upon-Thames, UK
| | - Nader I Al-Dewik
- School of Life Science, Pharmacy and Chemistry, Faculty of Science, Engineering & ComputingFaculty of Science, Engineering & Computing, Kingston University London, Kingston-Upon-Thames, UK.,Qatar Medical Genetic Center (QMGC), Hamad General Hospital (HGH), and Interim Translational Research Institute (iTRI), Hamad Medical Corporation (HMC), Doha, Qatar.,College of Health and Life Science (CHLS), Hamad Bin Khalifa University (HBKU), Doha, Qatar.,Department of Pediatrics, Women's Wellness and Research Center (WWRC), HMC, Doha, Qatar
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Annunziata M, Bonifacio M, Breccia M, Castagnetti F, Gozzini A, Iurlo A, Pregno P, Stagno F, Specchia G. Current Strategies and Future Directions to Achieve Deep Molecular Response and Treatment-Free Remission in Chronic Myeloid Leukemia. Front Oncol 2020; 10:883. [PMID: 32582549 PMCID: PMC7280484 DOI: 10.3389/fonc.2020.00883] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 05/05/2020] [Indexed: 12/21/2022] Open
Abstract
The treatment of chronic myeloid leukemia (CML) has been radically changed by the approval of tyrosine kinase inhibitors (TKIs), which target BCR-ABL1 kinase activity. CML is now managed as a chronic disease requiring long-term treatment and close molecular monitoring. It has been shown that in a substantial number of patients who have achieved a stable deep molecular response (DMR), TKI treatment can be safely discontinued without loss of response. Therefore, treatment-free remission (TFR), through the achievement of a DMR, is increasingly regarded as a feasible treatment goal in many CML patients. However, only nilotinib has approval in this setting and a number of controversial aspects remain regarding treatment choices and timings, predictive factors, patient communication, and optimal strategies to achieve successful TFR. This narrative review aims to provide a comprehensive overview on how to optimize the path to DMR and TFR in patients with CML, and discusses recent data and future directions.
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Affiliation(s)
| | | | - Massimo Breccia
- Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Fausto Castagnetti
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology “L. and A. Seràgnoli”, “S. Orsola-Malpighi” Univeristy Hospital, University of Bologna, Bologna, Italy
| | - Antonella Gozzini
- Department of Cellular Therapy and Transfusional Medicine, AUO Careggi, Florence, Italy
| | - Alessandra Iurlo
- Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Patrizia Pregno
- Hematology Division, Oncology and Hematology Department, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Fabio Stagno
- Division of Hematology and Bone Marrow Transplant, AOU Policlinico—V. Emanuele, Catania, Italy
| | - Giorgina Specchia
- Hematology Section, Department of Emergency and Organ Transplantation, University of Bari-Aldo Moro, Bari, Italy
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Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives. J Clin Med 2020; 9:jcm9061709. [PMID: 32498406 PMCID: PMC7357035 DOI: 10.3390/jcm9061709] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 05/27/2020] [Indexed: 02/07/2023] Open
Abstract
Ph+ chronic myeloid leukemia (CML) is a clonal myeloproliferative disease whose clinical course is characterized by progression disease from the early chronic phase (CP) to the fatal blastic phase (BP). This programmed course is closely related to the translocation t(9;22)(q22;q11) and the resulting BCR-ABL1 fusion protein (p210) that drives the leukemic transformation of hematopoietic stem cells. Therefore, the cure of CML can only pass through the abrogation of the Ph+ clone. Allogeneic stem cell transplantation (allo-SCT) and interferon-alpha (IFNα) have been proven to reduce the Ph+ clone in a limited proportion of CML population and this translated in a lower rate of progression to BP and in a significant prolongation of survival. Tyrosine-kinase inhibitors (TKIs), lastly introduced in 2000, by preventing the disease blastic transformation and significantly prolonging the survival in up to 90% of the patient population, radically changed the fate of CML. The current therapy with TKIs induces a chronicization of the disease but several criticisms still persist, and the most relevant one is the sustainability of long-term therapy with TKIs in terms of compliance, toxicity and costs. The perspectives concern the optimization of therapy according to the age, the risk of disease, the potency and the safety profiles of the TKIs. The prolongation of survival is the most important end point which should be guaranteed to all patients. The treatment free remission (TFR) is the new goal that we would like to give to an increasing number of patients. The cure remains the main objective of CML therapy.
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Bernardi S, Malagola M, Polverelli N, Russo D. Exosomes in Chronic Myeloid Leukemia: Are We Reading a New Reliable Message? Acta Haematol 2020; 143:509-510. [PMID: 31922494 DOI: 10.1159/000505088] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 11/27/2019] [Indexed: 01/27/2023]
MESH Headings
- Exosomes/metabolism
- Fusion Proteins, bcr-abl/genetics
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Neoplasm, Residual
- Polymerase Chain Reaction
- Protein Kinase Inhibitors/therapeutic use
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Affiliation(s)
- Simona Bernardi
- Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, Spedali Civili of Brescia, University of Brescia, Brescia, Italy,
| | - Michele Malagola
- Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, Spedali Civili of Brescia, University of Brescia, Brescia, Italy
| | - Nicola Polverelli
- Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, Spedali Civili of Brescia, University of Brescia, Brescia, Italy
| | - Domenico Russo
- Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, Spedali Civili of Brescia, University of Brescia, Brescia, Italy
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Balamurali D, Gorohovski A, Detroja R, Palande V, Raviv-Shay D, Frenkel-Morgenstern M. ChiTaRS 5.0: the comprehensive database of chimeric transcripts matched with druggable fusions and 3D chromatin maps. Nucleic Acids Res 2020; 48:D825-D834. [PMID: 31747015 PMCID: PMC7145514 DOI: 10.1093/nar/gkz1025] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 10/18/2019] [Accepted: 10/26/2019] [Indexed: 12/11/2022] Open
Abstract
Chimeric RNA transcripts are formed when exons from two genes fuse together, often due to chromosomal translocations, transcriptional errors or trans-splicing effect. While these chimeric RNAs produce functional proteins only in certain cases, they play a significant role in disease phenotyping and progression. ChiTaRS 5.0 (http://chitars.md.biu.ac.il/) is the latest and most comprehensive chimeric transcript repository, with 111 582 annotated entries from eight species, including 23 167 known human cancer breakpoints. The database includes unique information correlating chimeric breakpoints with 3D chromatin contact maps, generated from public datasets of chromosome conformation capture techniques (Hi-C). In this update, we have added curated information on druggable fusion targets matched with chimeric breakpoints, which are applicable to precision medicine in cancers. The introduction of a new section that lists chimeric RNAs in various cell-lines is another salient feature. Finally, using text-mining techniques, novel chimeras in Alzheimer's disease, schizophrenia, dyslexia and other diseases were collected in ChiTaRS. Thus, this improved version is an extensive catalogue of chimeras from multiple species. It extends our understanding of the evolution of chimeric transcripts in eukaryotes and contributes to the analysis of 3D genome conformational changes and the functional role of chimeras in the etiopathogenesis of cancers and other complex diseases.
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Affiliation(s)
- Deepak Balamurali
- Laboratory of Cancer Genomics and Biocomputing of Complex Diseases, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Alessandro Gorohovski
- Laboratory of Cancer Genomics and Biocomputing of Complex Diseases, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Rajesh Detroja
- Laboratory of Cancer Genomics and Biocomputing of Complex Diseases, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Vikrant Palande
- Laboratory of Cancer Genomics and Biocomputing of Complex Diseases, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Dorith Raviv-Shay
- Laboratory of Cancer Genomics and Biocomputing of Complex Diseases, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Milana Frenkel-Morgenstern
- Laboratory of Cancer Genomics and Biocomputing of Complex Diseases, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
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