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Soto CA, Lesch ML, Becker JL, Sharipol A, Khan A, Schafer XL, Becker MW, Munger JC, Frisch BJ. Elevated Lactate in the AML Bone Marrow Microenvironment Polarizes Leukemia-Associated Macrophages via GPR81 Signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2023.11.13.566874. [PMID: 39185193 PMCID: PMC11343108 DOI: 10.1101/2023.11.13.566874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Interactions between acute myeloid leukemia (AML) and the bone marrow microenvironment (BMME) are critical to leukemia progression and chemoresistance. In the solid tumor microenvironment, altered metabolite levels contribute to cancer progression. We performed a metabolomic analysis of AML patient bone marrow serum, revealing increased metabolites compared to age- and sex-matched controls. The most highly elevated metabolite in the AML BMME was lactate. Lactate signaling in solid tumors induces immunosuppressive tumor-associated macrophages and correlates with poor prognosis. This has not yet been studied in the leukemic BMME. Herein, we describe the role of lactate in the polarization of leukemia-associated macrophages (LAMs). Using a murine AML model of blast crisis chronic myelogenous leukemia (bcCML), we characterize the suppressive phenotype of LAMs by surface markers, transcriptomics, and cytokine profiling. Then, mice genetically lacking GPR81, the extracellular lactate receptor, were used to demonstrate GPR81 signaling as a mechanism of both the polarization of LAMs and the direct support of leukemia cells. Furthermore, elevated lactate diminished the function of hematopoietic progenitors and reduced stromal support for normal hematopoiesis. We report microenvironmental lactate as a mechanism of AML-induced immunosuppression and leukemic progression, thus identifying GPR81 signaling as an exciting and novel therapeutic target for treating this devastating disease.
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Affiliation(s)
- Celia A Soto
- Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine, Rochester, NY, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
| | - Maggie L Lesch
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Microbiology and Immunology, University of Rochester School of Medicine, Rochester, NY, USA
| | - Jennifer L Becker
- Genomics Research Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Azmeer Sharipol
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biomedical Engineering, University of Rochester School of Medicine, Rochester, NY, USA
| | - Amal Khan
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Microbiology and Immunology, University of Rochester School of Medicine, Rochester, NY, USA
| | - Xenia L Schafer
- Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, NY, USA
| | - Michael W Becker
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA
| | - Joshua C Munger
- Department of Microbiology and Immunology, University of Rochester School of Medicine, Rochester, NY, USA
- Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, NY, USA
| | - Benjamin J Frisch
- Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine, Rochester, NY, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biomedical Engineering, University of Rochester School of Medicine, Rochester, NY, USA
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2
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Liu D, Liu S, Ji Y, Jin Z, He Z, Hou M, Li D, Ma X. Lactylation modulation identifies key biomarkers and therapeutic targets in KMT2A-rearranged AML. Sci Rep 2025; 15:1511. [PMID: 39789150 PMCID: PMC11718094 DOI: 10.1038/s41598-025-86136-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 01/08/2025] [Indexed: 01/12/2025] Open
Abstract
Acute Myeloid Leukemia (AML) with KMT2A rearrangements (KMT2Ar), found on chromosome 11q23, is often called KMT2A-rearranged AML (KMT2Ar-AML). This variant is highly aggressive, characterized by rapid disease progression and poor outcomes. Growing knowledge of epigenetic changes, especially lactylation, has opened new avenues for investigation and management of this subtype. Lactylation plays a significant role in cancer, inflammation, and tissue regeneration, but the underlying mechanisms are not yet fully understood. This research examined the influence of lactylation on gene expression within KMT2Ar-AML, initially identifying twelve notable lactylation-dependent differentially expressed genes (DEGs). Using advanced machine learning techniques, six key lactylation-associated genes (PFN1, S100A6, CBR1, LDHB, LGALS1, PRDX1) were identified as essential for prognostic evaluation and linked to relevant disease pathways. The study also suggested PI3K inhibitors and Pevonedistat as possible therapeutic options to modulate immune cell infiltration. Our findings confirm the critical role of lactylation in KMT2Ar-AML and identify six key genes that may serve as biomarkers for diagnosis and treatment. In addition to highlighting the need for further validation in clinical settings, these findings contribute to our understanding of KMT2Ar-AML's molecular mechanisms.
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Grants
- No. wzyw2021012 Science and Technology Bureau of Wuzhong District, Suzhou, Jiangsu Province, China
- No. wzyw2021012 Science and Technology Bureau of Wuzhong District, Suzhou, Jiangsu Province, China
- No. wzyw2021012 Science and Technology Bureau of Wuzhong District, Suzhou, Jiangsu Province, China
- No. wzyw2021012 Science and Technology Bureau of Wuzhong District, Suzhou, Jiangsu Province, China
- No. 2020WSB03 Translational Research Grant of NCRCH
- No. 2020WSB03 Translational Research Grant of NCRCH
- No. 2020WSB03 Translational Research Grant of NCRCH
- No. 18KJA320005 Natural Science Foundation of the Jiangsu Higher Education Institution of China
- No. 18KJA320005 Natural Science Foundation of the Jiangsu Higher Education Institution of China
- No. 81900130 National Natural Science Foundation of China
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Affiliation(s)
- Dan Liu
- Soochow Hopes Hematonosis Hospital, Wudong Road 1339, Wuzhong District, Suzhou, 215100, China.
| | - Silu Liu
- Soochow Hopes Hematonosis Hospital, Wudong Road 1339, Wuzhong District, Suzhou, 215100, China
| | - Yujie Ji
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Ziyan Jin
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Zhewei He
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Mengjia Hou
- Soochow Hopes Hematonosis Hospital, Wudong Road 1339, Wuzhong District, Suzhou, 215100, China
| | - Dongyang Li
- Soochow Hopes Hematonosis Hospital, Wudong Road 1339, Wuzhong District, Suzhou, 215100, China
| | - Xiao Ma
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
- The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, China.
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Chen DW, Wafula EK, Kurre P. Trained and ready - the case for an inflammatory memory for hematopoietic stem and progenitor cells in the AML niche. Oncotarget 2024; 15:609-613. [PMID: 39236060 PMCID: PMC11376595 DOI: 10.18632/oncotarget.28642] [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: 09/07/2024] Open
Abstract
Lifelong hematopoiesis is sustained by crosstalk between hematopoietic stem and progenitor cells (HSPCs) and specialized bone marrow niches. Acute myeloid leukemia (AML) upends that balance, as leukemic blasts secrete factors that remodel the bone marrow into a self-reinforcing leukemic niche. The inflammatory secretome behind this compartmental adaptation accounts for a progressive decline in hematopoietic function that leads to diagnosis and persists through early treatment. Not surprisingly, the mediators of an acute inflammatory injury and HSPC suppression have attracted much attention in an effort to alleviate morbidity and improve outcomes. HSPCs typically recover during disease remission and re-expand in the bone marrow (BM), but little is known about potentially lasting consequences for stem cells and progenitors. We recently showed that AML-experienced HSPCs actively participate in the inflammatory process during leukemic progression. HSPCs are constituent components of the innate immune system, and elegant studies of infection and experimental inflammation over the past decade have described the generation of an adoptively transferable, innate immune memory. Building on this paradigm, we discuss the potential translational relevance of a durable legacy in AML-experienced HSPC.
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Affiliation(s)
- Ding-Wen Chen
- Department of Pediatrics, Comprehensive Bone Marrow Failure Center, Division of Hematology, Children's Hospital of Philadelphia, PA 19104, USA
| | - Eric K Wafula
- Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, PA 19104, USA
| | - Peter Kurre
- Department of Pediatrics, Comprehensive Bone Marrow Failure Center, Division of Hematology, Children's Hospital of Philadelphia, PA 19104, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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4
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Pietka G, De Lord C, Matthias G, Cheung B, Atwal S, Furtado M, Cullis J, Grey-Davies L, Narayanan S, McGregor A, Kilner M, Bosworth J, McMullin MF, Coats T, Parcharidou A, Cavenagh J, Byrne J, Iyengar S, Mohammed K, Cross N, Hubank M, Ribeiro S, Khorashad J, Wren D, O'Connor S, Taussig D. Capture-based targeted sequencing using a T-cell control in myeloid malignancies and idiopathic cytopenias. Br J Haematol 2024; 204:1325-1334. [PMID: 38462984 DOI: 10.1111/bjh.19377] [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: 11/21/2023] [Revised: 01/30/2024] [Accepted: 02/20/2024] [Indexed: 03/12/2024]
Abstract
We report on a study of next-generation sequencing in 257 patients undergoing investigations for cytopenias. We sequenced bone marrow aspirates using a target enrichment panel comprising 82 genes and used T cells from paired blood as a control. One hundred and sixty patients had idiopathic cytopenias, 81 had myeloid malignancies and 16 had lymphoid malignancies or other diagnoses. Forty-seven of the 160 patients with idiopathic cytopenias had evidence of somatic pathogenic variants consistent with clonal cytopenias. Only 39 genes of the 82 tested were mutated in the 241 patients with either idiopathic cytopenias or myeloid neoplasms. We confirm that T cells can be used as a control to distinguish between germline and somatic variants. The use of paired analysis with a T-cell control significantly reduced the time molecular scientists spent reporting compared to unpaired analysis. We identified somatic variants of uncertain significance (VUS) in a higher proportion (24%) of patients with myeloid malignancies or clonal cytopenias compared to less than 2% of patients with non-clonal cytopenias. This suggests that somatic VUS are indicators of a clonal process. Lastly, we show that blood depleted of lymphocytes can be used in place of bone marrow as a source of material for sequencing.
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Affiliation(s)
- Grzegorz Pietka
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Department of Translational Research, Royal Marsden Hospital NHS Trust, London, UK
| | - Corinne De Lord
- Department of Haematology, St Helier Hospital, London, UK
- Department of Haematology, Royal Marsden Hospital NHS Trust, London, UK
| | - Gwynn Matthias
- Department of Haematology, Queen Alexandra Hospital, Portsmouth, UK
| | - Betty Cheung
- Department of Haematology, Croydon University Hospital, London, UK
| | - Sangeeta Atwal
- Department of Haematology, Kingston Hospital NHS Foundation Trust, London, UK
| | - Michelle Furtado
- Department of Haematology, Royal Cornwall Hospitals NHS Foundation Trust, Cornwall, Truro, UK
| | - Jonathan Cullis
- Department of Haematology, Salisbury NHS Foundation Trust, Salisbury, UK
| | - Liz Grey-Davies
- Department of Haematology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK
| | | | - Andrew McGregor
- Department of Haematology, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Mari Kilner
- Department of Haematology, Northumbria Healthcare NHS Foundation Trust, Tyneside, UK
| | - Jenny Bosworth
- Department of Haematology, St Helier Hospital, London, UK
- Department of Haematology, Royal Marsden Hospital NHS Trust, London, UK
| | | | - Thomas Coats
- Department of Haematology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | | | - Jamie Cavenagh
- Department of Haematology, St Bartholomew's Hospital, London, UK
| | - Jenny Byrne
- Department of Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Sunil Iyengar
- Department of Haematology, Royal Marsden Hospital NHS Trust, London, UK
| | - Kabir Mohammed
- Department of Statistics, Royal Marsden Hospital NHS Trust, London, UK
| | - Nicholas Cross
- Faculty of Medicine, University of Southampton, Southampton, UK
- Wessex Genomics Laboratory Service, Salisbury NHS Foundation Trust, Salisbury, UK
| | - Mike Hubank
- Department of Translational Research, Royal Marsden Hospital Sutton, London, UK
- Division of Molecular Pathology, Clinical Genomics (Research), Institute of Cancer Research, London, UK
| | - Sara Ribeiro
- Department of Molecular Pathology, Royal Marsden Hospital Sutton, London, UK
| | - Jamshid Khorashad
- Department of Molecular Pathology, Royal Marsden Hospital Sutton, London, UK
| | - Dorte Wren
- Department of Molecular Pathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Simon O'Connor
- Department of Histopathology, Royal Marsden NHS Foundation Trust, London, UK
| | - David Taussig
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Department of Haematology, Royal Marsden Hospital NHS Trust, London, UK
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5
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Chen DW, Fan JM, Schrey JM, Mitchell DV, Jung SK, Hurwitz SN, Perez EB, Muraro MJ, Carroll M, Taylor DM, Kurre P. Inflammatory recruitment of healthy hematopoietic stem and progenitor cells in the acute myeloid leukemia niche. Leukemia 2024; 38:741-750. [PMID: 38228679 PMCID: PMC10997516 DOI: 10.1038/s41375-024-02136-7] [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: 08/03/2023] [Revised: 12/21/2023] [Accepted: 01/04/2024] [Indexed: 01/18/2024]
Abstract
Inflammation in the bone marrow (BM) microenvironment is a constitutive component of leukemogenesis in acute myeloid leukemia (AML). Current evidence suggests that both leukemic blasts and stroma secrete proinflammatory factors that actively suppress the function of healthy hematopoietic stem and progenitor cells (HSPCs). HSPCs are also cellular components of the innate immune system, and we reasoned that they may actively propagate the inflammation in the leukemic niche. In two separate congenic models of AML we confirm by evaluation of the BM plasma secretome and HSPC-selective single-cell RNA sequencing (scRNA-Seq) that multipotent progenitors and long-lived stem cells adopt inflammatory gene expression programs, even at low leukemic infiltration of the BM. In particular, we observe interferon gamma (IFN-γ) pathway activation, along with secretion of its chemokine target, CXCL10. We show that AML-derived nanometer-sized extracellular vesicles (EVAML) are sufficient to trigger this inflammatory HSPC response, both in vitro and in vivo. Altogether, our studies indicate that HSPCs are an unrecognized component of the inflammatory adaptation of the BM by leukemic cells. The pro-inflammatory conversion and long-lived presence of HSPCs in the BM along with their regenerative re-expansion during remission may impact clonal selection and disease evolution.
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Affiliation(s)
- Ding-Wen Chen
- Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Jian-Meng Fan
- Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Julie M Schrey
- Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Dana V Mitchell
- Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Seul K Jung
- Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Stephanie N Hurwitz
- Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | | | | | - Martin Carroll
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Deanne M Taylor
- Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Peter Kurre
- Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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6
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Ibneeva L, Singh SP, Sinha A, Eski SE, Wehner R, Rupp L, Kovtun I, Pérez-Valencia JA, Gerbaulet A, Reinhardt S, Wobus M, von Bonin M, Sancho J, Lund F, Dahl A, Schmitz M, Bornhäuser M, Chavakis T, Wielockx B, Grinenko T. CD38 promotes hematopoietic stem cell dormancy. PLoS Biol 2024; 22:e3002517. [PMID: 38422172 DOI: 10.1371/journal.pbio.3002517] [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: 07/11/2023] [Revised: 03/12/2024] [Accepted: 01/24/2024] [Indexed: 03/02/2024] Open
Abstract
A subpopulation of deeply quiescent, so-called dormant hematopoietic stem cells (dHSCs) resides at the top of the hematopoietic hierarchy and serves as a reserve pool for HSCs. The state of dormancy protects the HSC pool from exhaustion throughout life; however, excessive dormancy may prevent an efficient response to hematological stresses. Despite the significance of dHSCs, the mechanisms maintaining their dormancy remain elusive. Here, we identify CD38 as a novel and broadly applicable surface marker for the enrichment of murine dHSCs. We demonstrate that cyclic adenosine diphosphate ribose (cADPR), the product of CD38 cyclase activity, regulates the expression of the transcription factor c-Fos by increasing the release of Ca2+ from the endoplasmic reticulum (ER). Subsequently, we uncover that c-Fos induces the expression of the cell cycle inhibitor p57Kip2 to drive HSC dormancy. Moreover, we found that CD38 ecto-enzymatic activity at the neighboring CD38-positive cells can promote human HSC quiescence. Together, CD38/cADPR/Ca2+/c-Fos/p57Kip2 axis maintains HSC dormancy. Pharmacological manipulations of this pathway can provide new strategies to improve the success of stem cell transplantation and blood regeneration after injury or disease.
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Affiliation(s)
- Liliia Ibneeva
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | | | - Anupam Sinha
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Sema Elif Eski
- IRIBHM, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Rebekka Wehner
- Institute for Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Luise Rupp
- Institute for Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Iryna Kovtun
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Juan Alberto Pérez-Valencia
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Alexander Gerbaulet
- Institute for Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Susanne Reinhardt
- DRESDEN-concept Genome Center, Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany
| | - Manja Wobus
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Clinic I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Malte von Bonin
- Medical Clinic I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Jaime Sancho
- Instituto de Parasitología y Biomedicina "López-Neyra" CSIC, Granada, Spain
| | - Frances Lund
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Andreas Dahl
- DRESDEN-concept Genome Center, Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany
| | - Marc Schmitz
- Institute for Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martin Bornhäuser
- National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Clinic I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Ben Wielockx
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- Experimental Center, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Tatyana Grinenko
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Jiao Tong University School of Medicine, Shanghai, China
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7
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Tissot FS, Gonzalez-Anton S, Lo Celso C. Intravital Microscopy to Study the Effect of Matrix Metalloproteinase Inhibition on Acute Myeloid Leukemia Cell Migration in the Bone Marrow. Methods Mol Biol 2024; 2747:211-227. [PMID: 38038943 DOI: 10.1007/978-1-0716-3589-6_17] [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] [Indexed: 12/02/2023]
Abstract
Hematopoiesis is the process through which all mature blood cells are formed and takes place in the bone marrow (BM). Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. AML progression causes drastic remodeling of the BM microenvironment, making it no longer supportive of healthy hematopoiesis and leading to clinical cytopenia in patients. Understanding the mechanisms by which AML cells shape the BM to their benefit would lead to the development of new therapeutic strategies. While the role of extracellular matrix (ECM) in solid cancer has been extensively studied during decades, its role in the BM and in leukemia progression has only begun to be acknowledged. In this context, intravital microscopy (IVM) gives the unique insight of direct in vivo observation of AML cell behavior in their environment during disease progression and/or upon drug treatments. Here we describe our protocol for visualizing and analyzing MLL-AF9 AML cell dynamics upon systemic inhibition of matrix metalloproteinases (MMP), combining confocal and two-photon microscopy and focusing on cell migration.
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Affiliation(s)
- Floriane S Tissot
- Department of Life Sciences, Imperial College London, London, UK
- The Francis Crick Institute, London, UK
| | - Sara Gonzalez-Anton
- Department of Life Sciences, Imperial College London, London, UK
- The Francis Crick Institute, London, UK
| | - Cristina Lo Celso
- Department of Life Sciences, Imperial College London, London, UK.
- The Francis Crick Institute, London, UK.
- Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK.
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8
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Jia B, Zhao C, Minagawa K, Shike H, Claxton DF, Ehmann WC, Rybka WB, Mineishi S, Wang M, Schell TD, Prabhu KS, Paulson RF, Zhang Y, Shultz LD, Zheng H. Acute Myeloid Leukemia Causes T Cell Exhaustion and Depletion in a Humanized Graft-versus-Leukemia Model. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:1426-1437. [PMID: 37712758 DOI: 10.4049/jimmunol.2300111] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 08/21/2023] [Indexed: 09/16/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation (alloSCT) is, in many clinical settings, the only curative treatment for acute myeloid leukemia (AML). The clinical benefit of alloSCT greatly relies on the graft-versus-leukemia (GVL) effect. However, AML relapse remains the top cause of posttransplant death; this highlights the urgent need to enhance GVL. Studies of human GVL have been hindered by the lack of optimal clinically relevant models. In this article, we report, the successful establishment of a novel (to our knowledge) humanized GVL model system by transplanting clinically paired donor PBMCs and patient AML into MHC class I/II knockout NSG mice. We observed significantly reduced leukemia growth in humanized mice compared with mice that received AML alone, demonstrating a functional GVL effect. Using this model system, we studied human GVL responses against human AML cells in vivo and discovered that AML induced T cell depletion, likely because of increased T cell apoptosis. In addition, AML caused T cell exhaustion manifested by upregulation of inhibitory receptors, increased expression of exhaustion-related transcription factors, and decreased T cell function. Importantly, combined blockade of human T cell-inhibitory pathways effectively reduced leukemia burden and reinvigorated CD8 T cell function in this model system. These data, generated in a highly clinically relevant humanized GVL model, not only demonstrate AML-induced inhibition of alloreactive T cells but also identify promising therapeutic strategies targeting T cell depletion and exhaustion for overcoming GVL failure and treating AML relapse after alloSCT.
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Affiliation(s)
- Bei Jia
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA
| | - Chenchen Zhao
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA
| | - Kentaro Minagawa
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA
| | - Hiroko Shike
- Department of Pathology, Penn State University College of Medicine, Hershey, PA
| | - David F Claxton
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA
| | - W Christopher Ehmann
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA
| | - Witold B Rybka
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA
| | - Shin Mineishi
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA
| | - Ming Wang
- Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH
| | - Todd D Schell
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA
- Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA
| | - K Sandeep Prabhu
- Department of Veterinary and Biomedical Sciences, Penn State University, University Park, PA
| | - Robert F Paulson
- Department of Veterinary and Biomedical Sciences, Penn State University, University Park, PA
| | - Yi Zhang
- Center for Discovery and Innovation, Hackensack Meridian Health, Edison, NJ
| | - Leonard D Shultz
- Department of Immunology, The Jackson Laboratory, Bar Harbor, ME
| | - Hong Zheng
- Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA
- Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA
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9
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Jensen CT, Åhsberg J, Tingvall-Gustafsson J, Somasundaram R, Lang S, Ungerbäck J, Porwit A, Soneji S, Sigvardsson M. B-lineage acute lymphoblastic leukemia causes cellautonomous defects in long-term hematopoietic stem cell function. Haematologica 2023; 108:3175-3180. [PMID: 36861396 PMCID: PMC10620591 DOI: 10.3324/haematol.2022.282430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Affiliation(s)
| | - Josefine Åhsberg
- Department of Clinical and Experimental Medicine, Linköping University
| | | | | | - Stefan Lang
- Division of Molecular Hematology, Lund University, Lund
| | | | - Anna Porwit
- Division of Pathology, Lund University, Lund
| | - Shamit Soneji
- Division of Molecular Hematology, Lund University, Lund
| | - Mikael Sigvardsson
- Division of Molecular Hematology, Lund University, Lund, Sweden; Department of Clinical and Experimental Medicine, Linköping University.
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10
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Liesveld J, Galipeau J. In Vitro Insights Into the Influence of Marrow Mesodermal/Mesenchymal Progenitor Cells on Acute Myelogenous Leukemia and Myelodysplastic Syndromes. Stem Cells 2023; 41:823-836. [PMID: 37348128 DOI: 10.1093/stmcls/sxad050] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 06/09/2023] [Indexed: 06/24/2023]
Abstract
The study of marrow-resident mesodermal progenitors can provide important insight into their role in influencing normal and aberrant hematopoiesis as occurs in acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). In addition, the chemokine competency of these cells provides links to the inflammatory milieu of the marrow microenvironment with additional implications for normal and malignant hematopoiesis. While in vivo studies have elucidated the structure and function of the marrow niche in murine genetic models, corollary human studies have not been feasible, and thus the use of culture-adapted mesodermal cells has provided insights into the role these rare endogenous niche cells play in physiologic, malignant, and inflammatory states. This review focuses on culture-adapted human mesenchymal stem/stromal cells (MSCs) as they have been utilized in understanding their influence in AML and MDS as well as on their chemokine-mediated responses to myeloid malignancies, injury, and inflammation. Such studies have intrinsic limitations but have provided mechanistic insights and clues regarding novel druggable targets.
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Affiliation(s)
- Jane Liesveld
- Department of Medicine, James P. Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
| | - Jaques Galipeau
- University of Wisconsin School of Medicine and Public Health, University of Wisconsin in Madison, Madison, WI, USA
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11
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Harris B, Singh DK, Verma M, Fahl SP, Rhodes M, Sprinkle SR, Wang M, Zhang Y, Perrigoue J, Kessel R, Peri S, West J, Giricz O, Boultwood J, Pellagatti A, Ramesh KH, Montagna C, Pradhan K, Tyner JW, Kennedy BK, Holinstat M, Steidl U, Sykes S, Verma A, Wiest DL. Ribosomal protein control of hematopoietic stem cell transformation through direct, non-canonical regulation of metabolism. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.31.543132. [PMID: 37398007 PMCID: PMC10312568 DOI: 10.1101/2023.05.31.543132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
We report here that expression of the ribosomal protein, RPL22, is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from increased expression of the Rpl22 target, ALOX12, an upstream regulator of fatty acid oxidation (FAO). The increased FAO mediated by Rpl22-deficiency also persists in leukemia cells and promotes their survival. Altogether, these findings reveal that Rpl22 insufficiency enhances the leukemia potential of HSC via non-canonical de-repression of its target, ALOX12, which enhances FAO, a process that may serve as a therapeutic vulnerability of Rpl22 low MDS and AML leukemia cells. Highlights RPL22 insufficiency is observed in MDS/AML and is associated with reduced survivalRpl22-deficiency produces an MDS-like syndrome and facilitates leukemogenesisRpl22-deficiency does not impair global protein synthesis by HSCRpl22 controls leukemia cell survival by non-canonical regulation of lipid oxidation eTOC: Rpl22 controls the function and transformation potential of hematopoietic stem cells through effects on ALOX12 expression, a regulator of fatty acid oxidation.
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12
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Casado P, Cutillas PR. Proteomic Characterization of Acute Myeloid Leukemia for Precision Medicine. Mol Cell Proteomics 2023; 22:100517. [PMID: 36805445 PMCID: PMC10152134 DOI: 10.1016/j.mcpro.2023.100517] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023] Open
Abstract
Acute myeloid leukemia (AML) is a highly heterogeneous cancer of the hematopoietic system with no cure for most patients. In addition to chemotherapy, treatment options for AML include recently approved therapies that target proteins with roles in AML pathobiology, such as FLT3, BLC2, and IDH1/2. However, due to disease complexity, these therapies produce very diverse responses, and survival rates are still low. Thus, despite considerable advances, there remains a need for therapies that target different aspects of leukemic biology and for associated biomarkers that define patient populations likely to respond to each available therapy. To meet this need, drugs that target different AML vulnerabilities are currently in advanced stages of clinical development. Here, we review proteomics and phosphoproteomics studies that aimed to provide insights into AML biology and clinical disease heterogeneity not attainable with genomic approaches. To place the discussion in context, we first provide an overview of genetic and clinical aspects of the disease, followed by a summary of proteins targeted by compounds that have been approved or are under clinical trials for AML treatment and, if available, the biomarkers that predict responses. We then discuss proteomics and phosphoproteomics studies that provided insights into AML pathogenesis, from which potential biomarkers and drug targets were identified, and studies that aimed to rationalize the use of synergistic drug combinations. When considered as a whole, the evidence summarized here suggests that proteomics and phosphoproteomics approaches can play a crucial role in the development and implementation of precision medicine for AML patients.
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Affiliation(s)
- Pedro Casado
- Cell Signalling & Proteomics Group, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Pedro R Cutillas
- Cell Signalling & Proteomics Group, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; The Alan Turing Institute, The British Library, London, United Kingdom; Digital Environment Research Institute (DERI), Queen Mary University of London, London, United Kingdom.
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13
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Teixeira A, Carreira L, Abalde-Cela S, Sampaio-Marques B, Areias AC, Ludovico P, Diéguez L. Current and Emerging Techniques for Diagnosis and MRD Detection in AML: A Comprehensive Narrative Review. Cancers (Basel) 2023; 15:cancers15051362. [PMID: 36900154 PMCID: PMC10000116 DOI: 10.3390/cancers15051362] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/06/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
Acute myeloid leukemia (AML) comprises a group of hematologic neoplasms characterized by abnormal differentiation and proliferation of myeloid progenitor cells. AML is associated with poor outcome due to the lack of efficient therapies and early diagnostic tools. The current gold standard diagnostic tools are based on bone marrow biopsy. These biopsies, apart from being very invasive, painful, and costly, have low sensitivity. Despite the progress uncovering the molecular pathogenesis of AML, the development of novel detection strategies is still poorly explored. This is particularly important for patients that check the criteria for complete remission after treatment, since they can relapse through the persistence of some leukemic stem cells. This condition, recently named as measurable residual disease (MRD), has severe consequences for disease progression. Hence, an early and accurate diagnosis of MRD would allow an appropriate therapy to be tailored, improving a patient's prognosis. Many novel techniques with high potential in disease prevention and early detection are being explored. Among them, microfluidics has flourished in recent years due to its ability at processing complex samples as well as its demonstrated capacity to isolate rare cells from biological fluids. In parallel, surface-enhanced Raman scattering (SERS) spectroscopy has shown outstanding sensitivity and capability for multiplex quantitative detection of disease biomarkers. Together, these technologies can allow early and cost-effective disease detection as well as contribute to monitoring the efficiency of treatments. In this review, we aim to provide a comprehensive overview of AML disease, the conventional techniques currently used for its diagnosis, classification (recently updated in September 2022), and treatment selection, and we also aim to present how novel technologies can be applied to improve the detection and monitoring of MRD.
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Affiliation(s)
- Alexandra Teixeira
- International Iberian Nanotechnology Laboratory (INL), Avda Mestre José Veiga, 4715-310 Braga, Portugal
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s–PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Luís Carreira
- International Iberian Nanotechnology Laboratory (INL), Avda Mestre José Veiga, 4715-310 Braga, Portugal
| | - Sara Abalde-Cela
- International Iberian Nanotechnology Laboratory (INL), Avda Mestre José Veiga, 4715-310 Braga, Portugal
| | - Belém Sampaio-Marques
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s–PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Anabela C. Areias
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s–PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Paula Ludovico
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s–PT Government Associate Laboratory, 4710-057 Braga, Portugal
- Correspondence: (P.L.); (L.D.)
| | - Lorena Diéguez
- International Iberian Nanotechnology Laboratory (INL), Avda Mestre José Veiga, 4715-310 Braga, Portugal
- Correspondence: (P.L.); (L.D.)
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14
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Li G, Chen T, Dahlman J, Eniola‐Adefeso L, Ghiran IC, Kurre P, Lam WA, Lang JK, Marbán E, Martín P, Momma S, Moos M, Nelson DJ, Raffai RL, Ren X, Sluijter JPG, Stott SL, Vunjak‐Novakovic G, Walker ND, Wang Z, Witwer KW, Yang PC, Lundberg MS, Ochocinska MJ, Wong R, Zhou G, Chan SY, Das S, Sundd P. Current challenges and future directions for engineering extracellular vesicles for heart, lung, blood and sleep diseases. J Extracell Vesicles 2023; 12:e12305. [PMID: 36775986 PMCID: PMC9923045 DOI: 10.1002/jev2.12305] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/19/2022] [Accepted: 01/09/2022] [Indexed: 02/14/2023] Open
Abstract
Extracellular vesicles (EVs) carry diverse bioactive components including nucleic acids, proteins, lipids and metabolites that play versatile roles in intercellular and interorgan communication. The capability to modulate their stability, tissue-specific targeting and cargo render EVs as promising nanotherapeutics for treating heart, lung, blood and sleep (HLBS) diseases. However, current limitations in large-scale manufacturing of therapeutic-grade EVs, and knowledge gaps in EV biogenesis and heterogeneity pose significant challenges in their clinical application as diagnostics or therapeutics for HLBS diseases. To address these challenges, a strategic workshop with multidisciplinary experts in EV biology and U.S. Food and Drug Administration (USFDA) officials was convened by the National Heart, Lung and Blood Institute. The presentations and discussions were focused on summarizing the current state of science and technology for engineering therapeutic EVs for HLBS diseases, identifying critical knowledge gaps and regulatory challenges and suggesting potential solutions to promulgate translation of therapeutic EVs to the clinic. Benchmarks to meet the critical quality attributes set by the USFDA for other cell-based therapeutics were discussed. Development of novel strategies and approaches for scaling-up EV production and the quality control/quality analysis (QC/QA) of EV-based therapeutics were recognized as the necessary milestones for future investigations.
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Affiliation(s)
- Guoping Li
- Cardiovascular Research CenterMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Tianji Chen
- Department of Pediatrics, College of MedicineUniversity of Illinois at ChicagoChicagoIllinoisUSA
| | - James Dahlman
- Department of Biomedical EngineeringGeorgia Institute of Technology and Emory University School of MedicineAtlantaGeorgiaUSA
| | - Lola Eniola‐Adefeso
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMichiganUSA
| | - Ionita C. Ghiran
- Department of Anesthesia and Pain MedicineBeth Israel Deaconess Medical Center, and Harvard Medical SchoolBostonMassachusettsUSA
| | - Peter Kurre
- Children's Hospital of Philadelphia, Comprehensive Bone Marrow Failure Center, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Wilbur A. Lam
- Wallace H. Coulter Department of Biomedical Engineering, Department of PediatricsEmory School of MedicineAflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University and Georgia Institute of TechnologyAtlantaGeorgiaUSA
| | - Jennifer K. Lang
- Department of Medicine, Division of Cardiology, Jacobs School of Medicine and Biomedical SciencesVeterans Affairs Western New York Healthcare SystemBuffaloNew YorkUSA
| | - Eduardo Marbán
- Smidt Heart InstituteCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Pilar Martín
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV)MadridSpain
| | - Stefan Momma
- Institute of Neurology (Edinger Institute)University HospitalGoethe UniversityFrankfurt am MainGermany
| | - Malcolm Moos
- Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and ResearchUnited States Food and Drug AdministrationSilver SpringMarylandUSA
| | - Deborah J. Nelson
- Department of Pharmacological and Physiological SciencesThe University of ChicagoChicagoIllinoisUSA
| | - Robert L. Raffai
- Department of Veterans Affairs, Surgical Service (112G)San Francisco VA Medical CenterSan FranciscoCaliforniaUSA
- Department of Surgery, Division of Vascular and Endovascular SurgeryUniversity of CaliforniaSan FranciscoCaliforniaUSA
| | - Xi Ren
- Department of Biomedical EngineeringCarnegie Mellon UniversityPittsburghPennsylvaniaUSA
| | - Joost P. G. Sluijter
- Department of Experimental Cardiology, Circulatory Health LaboratoryRegenerative Medicine Centre, UMC Utrecht, University UtrechtUtrechtThe Netherlands
| | - Shannon L. Stott
- Massachusetts General Hospital Cancer Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Gordana Vunjak‐Novakovic
- Department of Biomedical Engineering, Department of MedicineColumbia UniversityNew YorkNew YorkUSA
| | - Nykia D. Walker
- Department of Biological SciencesUniversity of Maryland Baltimore CountyBaltimoreMarylandUSA
| | - Zhenjia Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical SciencesWashington State UniversitySpokaneWashingtonUSA
| | - Kenneth W. Witwer
- Department of Molecular and Comparative Pathobiology, Department of Neurology and Neurosurgeryand The Richman Family Precision Medicine Center of Excellence in Alzheimer's DiseaseThe Johns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Phillip C. Yang
- Division of Cardiovascular Medicine, Department of MedicineStanford University School of MedicineStanfordCaliforniaUSA
| | - Martha S. Lundberg
- Division of Cardiovascular Sciences, National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Margaret J. Ochocinska
- Division of Blood Diseases and Resources, National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Renee Wong
- Division of Cardiovascular Sciences, National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Guofei Zhou
- Division of Lung Diseases, National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Stephen Y. Chan
- Pittsburgh Heart, Lung and Blood Vascular Medicine InstituteUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA
- Division of Cardiology and Department of MedicineUniversity of Pittsburgh School of Medicine and University of Pittsburgh Medical CenterPittsburghPennsylvaniaUSA
| | - Saumya Das
- Cardiovascular Research CenterMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Prithu Sundd
- Pittsburgh Heart, Lung and Blood Vascular Medicine InstituteUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA
- Division of Pulmonary Allergy and Critical Care Medicine and Department of MedicineUniversity of PittsburghPittsburghPennsylvaniaUSA
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15
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Sadovskaya AV, Petinati NA, Kapranov NM, Drize NI, Vasil'eva AN, Aleshina OA, Parovichnikova EN. Dynamics of Changes in the Properties of Multipotent Mesenchymal Stromal Cells in Patients with Acute Leukemia. Bull Exp Biol Med 2023; 174:556-563. [PMID: 36894815 DOI: 10.1007/s10517-023-05747-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Indexed: 03/11/2023]
Abstract
In acute leukemia, the stromal microenvironment of the bone marrow that regulates hematopoiesis is modified under the influence of malignant cells. Chemotherapy also adversely affects stromal cells. Multipotent mesenchymal stromal cells (MSC) are involved in the formation of the stromal microenvironment and in the regulation of normal and tumor hematopoietic cells. The properties of MSC from the bone marrow of patients with acute myeloid and lymphoid leukemia were studied at the onset of the disease and after achieving remission. The immunophenotype and the level of gene expression were analyzed in MSC of 34 patients. In MSC from patients with acute leukemia, the expression of CD105 and CD274 was significantly reduced in comparison with MSC from healthy donors. At the onset of the disease, the expression of IL6, JAG1, PPARG, IGF1, and PDGFRA was enhanced, while the expression of IL1B, IL8, SOX9, ANG1, and TGFB was reduced. All these changes affect the course of the disease in patients and can be the targets of therapeutic intervention.
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Affiliation(s)
- A V Sadovskaya
- National Medical Research Center of Hematology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - N A Petinati
- National Medical Research Center of Hematology, Ministry of Health of the Russian Federation, Moscow, Russia.
| | - N M Kapranov
- National Medical Research Center of Hematology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - N I Drize
- National Medical Research Center of Hematology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - A N Vasil'eva
- National Medical Research Center of Hematology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - O A Aleshina
- National Medical Research Center of Hematology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - E N Parovichnikova
- National Medical Research Center of Hematology, Ministry of Health of the Russian Federation, Moscow, Russia
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16
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Shahrokh B, Allahbakhshian FM, Ahmad G, Fatemeh F, Hossein MM. AML-derived extracellular vesicles negatively regulate stem cell pool size: A step toward bone marrow failure. Curr Res Transl Med 2023; 71:103375. [PMID: 36508911 DOI: 10.1016/j.retram.2022.103375] [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: 11/13/2021] [Revised: 11/16/2022] [Accepted: 11/29/2022] [Indexed: 12/05/2022]
Abstract
PURPOSE OF THE STUDY Long-term repopulating hematopoietic stem cells (LTR-HSCs) have been previously shown to reside in close proximity to osteoblasts, where they take shelter in the bone marrow (BM) microenvironment against cytotoxic and apoptotic stimuli. Nevertheless, the function of the HSC niche is believed to undergo an adaptive evolutionary modification during leukemogenesis. Recent studies have demonstrated that leukemic clones can impact BM homing through extracellular vesicle (EV) secretion. However, the exact mechanism driving BM conversion is still unclear. In the present study, the human osteoblast cell line (MG-63) were subjected to various concentration of sera-derived EVs of patients with acute myeloid leukemia (AML) and healthy volunteers to assess if they are associated strongly enough to alter the expression pattern of cross-talk molecules involved in niche interactions. METHOD To gain a brief insight into the EVs secretion criteria, we first conducted a comparative analysis of sera-derived EVs by dynamic light scattering (DLS), transmission electron microscopy (TEM), and Bradford assay. After incubating MG-63 cell lines with increasing concentrations of the EVs, Trypan-blue and microculture tetrazolium test (MTT) assays were used to evaluate the cell survival, logarithmic growth, and metabolic activity. Finally, the expression levels of OPN, ANGPT-1, and JAG-1 transcripts were evaluated through the qRT-PCR technique. RESULTS Here, we report that AML-derived EVs can affect the viability, cell growth, and metabolic activity of the human osteoblasts cell line (MG-63) compared to those that received healthy-derived EVs. We also found that leukemic EVs tend to induce overexpression of OPN but reduce the expression of ANGPT-1 and JAG-1 genes in the osteoblast transcriptome, which may provide a potential context imposing selective suppression of HSC pool size. CONCLUSION These findings extend the general concept of a novel mechanism in which leukemic EVs would make it possible to create a specialized pre-metastatic microenvironment in the interest of tumor expansion, allowing leukemic clones to overcome their HSCs counterparts.
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Affiliation(s)
- Bahrampour Shahrokh
- Laboratory Hematology and Blood Banking, School of Allied Medical Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farsani Mehdi Allahbakhshian
- Laboratory Hematology and Blood Banking, School of Allied Medical Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran; HSCT Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Gharehbaghian Ahmad
- Laboratory Hematology and Blood Banking, School of Allied Medical Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Feizi Fatemeh
- Laboratory Hematology and Blood Banking, School of Allied Medical Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadi Mohammad Hossein
- Laboratory Hematology and Blood Banking, School of Allied Medical Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran; HSCT Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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17
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Kumasaka S, Kubota J, Kumasaka Y, Naito C, Tsushima Y. A novel use of CT attenuation value: increased bone marrow density in patients with acute myeloid leukemia. Acta Radiol 2022; 64:1573-1578. [PMID: 36317293 DOI: 10.1177/02841851221135154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Background Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Bone marrow computed tomography (CT) attenuation may increase in patients with myeloproliferative disorders; however, the actual threshold CT attenuation value predictive of myeloproliferative has not been reported. Purpose To determine whether the unenhanced CT attenuation value of the bone marrow may be useful for predicting AML. Material and Methods We retrospectively analyzed patients with AML (n = 56) who underwent unenhanced CT before treatment, and age- and sex-matched controls without any hematologic disease. For each patient, the CT attenuation value (HU) of the iliac bone was measured and compared between the two groups. Receiver operating characteristic (ROC) curve analysis was used to define the cutoff value for predicting AML on all patients, and only on late elderly patients (aged ≥75 years). Results Patients with AML showed higher bone marrow CT attenuation value (131.4 ± 58.3 vs. 53.9 ± 67.2 HU; P < 0.001), compared to the controls. The sensitivity and specificity for the diagnosis of AML in all patients were 78.6% and 80.4%, respectively, at a threshold value of 90 HU, whereas they were 83.3% and 91.7%, respectively, at 40 HU in late elderly patients. Conclusion The iliac bone CT attenuation value was elevated in patients with AML and may be useful for predicting AML.
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Affiliation(s)
- Soma Kumasaka
- Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Jun Kubota
- Department of Radiology, Saiseikai Maebashi Hospital, Maebashi, Gunma, Japan
| | - Yuka Kumasaka
- Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Chiaki Naito
- Department of Hematology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Yoshito Tsushima
- Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
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18
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Jackmann N, Englund S, Frisk P, Mäkitie O, Utriainen P, Mörtberg A, Henriques-Normark B, Pütsep K, Harila-Saari A. The human cathelicidin hCAP-18 in serum of children with haemato-oncological diseases. Br J Haematol 2022; 198:1023-1031. [PMID: 35849644 PMCID: PMC9543647 DOI: 10.1111/bjh.18360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/29/2022] [Accepted: 07/04/2022] [Indexed: 11/29/2022]
Abstract
The human cathelicidin hCAP‐18 (pro‐LL‐37) is the pro‐protein of the antimicrobial peptide LL‐37. hCAP‐18 can be produced by many different cell types; bone marrow neutrophil precursors are the main source of hCAP‐18 in the circulation. Neutrophil count is used as a marker for myelopoiesis but does not always reflect neutrophil production in the bone marrow, and thus additional markers are needed. In this study, we established the reference interval of serum hCAP‐18 level in healthy children and compared serum hCAP‐18 levels between different diagnostic groups of children with haemato‐oncological diseases, at diagnosis. We found that children with diseases that impair myelopoiesis, such as acute leukaemia, aplastic anaemia, or myelodysplastic syndrome, presented with low hCAP‐18 levels, whereas patients with non‐haematological malignancies displayed serum hCAP‐18 levels in the same range as healthy children. Children with chronic myeloid leukaemia presented with high circulating levels of hCAP‐18, probably reflecting the high number of all differentiation stages of myeloid cells. We suggest that analysis of serum hCAP‐18 provides additional information regarding myelopoiesis in children with haemato‐oncological diseases, which may have future implications in assessment of myelopoiesis in clinical management.
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Affiliation(s)
- Natalja Jackmann
- Department of Women's and Children's Health, Uppsala University and University Children's Hospital, Uppsala, Sweden
| | - Sofia Englund
- Department of Women's and Children's Health, Uppsala University and University Children's Hospital, Uppsala, Sweden
| | - Per Frisk
- Department of Women's and Children's Health, Uppsala University and University Children's Hospital, Uppsala, Sweden
| | - Outi Mäkitie
- Department of Molecular Medicine and Surgery, Karolinska Institute, and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.,Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Pauliina Utriainen
- Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Anette Mörtberg
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Birgitta Henriques-Normark
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden
| | - Katrin Pütsep
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.,Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Arja Harila-Saari
- Department of Women's and Children's Health, Uppsala University and University Children's Hospital, Uppsala, Sweden
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19
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Maynard RS, Hellmich C, Bowles KM, Rushworth SA. Acute Myeloid Leukaemia Drives Metabolic Changes in the Bone Marrow Niche. Front Oncol 2022; 12:924567. [PMID: 35847950 PMCID: PMC9277016 DOI: 10.3389/fonc.2022.924567] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/03/2022] [Indexed: 11/30/2022] Open
Abstract
Acute myeloid leukaemia (AML) is a highly proliferative cancer characterised by infiltration of immature haematopoietic cells in the bone marrow (BM). AML predominantly affects older people and outcomes, particularly in this difficult to treat population remain poor, in part due to inadequate response to therapy, and treatment toxicity. Normal haematopoiesis is supported by numerous support cells within the BM microenvironment or niche, including adipocytes, stromal cells and endothelial cells. In steady state haematopoiesis, haematopoietic stem cells (HSCs) primarily acquire ATP through glycolysis. However, during stress-responses HSCs rapidly transition to oxidative phosphorylation, enabled by mitochondrial plasticity. Historically it was thought that cancer cells preferentially used glycolysis for ATP production, however recently it has become evident that many cancers, including AML primarily use the TCA cycle and oxidative phosphorylation for rapid proliferation. AML cells hijack the stress-response pathways of their non-malignant counterparts, utilising mitochondrial changes to drive expansion. In addition, amino acids are also utilised by leukaemic stem cells to aid their metabolic output. Together, these processes allow AML cells to maximise their ATP production, using multiple metabolites and fuelling rapid cell turnover which is a hallmark of the disease. This review of AML derived changes in the BM niche, which enable enhanced metabolism, will consider the important pathways and discuss future challenges with a view to understanding how AML cells are able to hijack metabolic pathways and how we may elucidate new targets for potential therapies.
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Affiliation(s)
- Rebecca S. Maynard
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
| | - Charlotte Hellmich
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
- Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, United Kingdom
| | - Kristian M. Bowles
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
- Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, United Kingdom
| | - Stuart A. Rushworth
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
- *Correspondence: Stuart A. Rushworth,
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20
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Pirillo C, Birch F, Tissot FS, Anton SG, Haltalli M, Tini V, Kong I, Piot C, Partridge B, Pospori C, Keeshan K, Santamaria S, Hawkins E, Falini B, Marra A, Duarte D, Lee CF, Roberts E, Lo Celso C. Metalloproteinase inhibition reduces AML growth, prevents stem cell loss, and improves chemotherapy effectiveness. Blood Adv 2022; 6:3126-3141. [PMID: 35157757 PMCID: PMC9131921 DOI: 10.1182/bloodadvances.2021004321] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 01/25/2022] [Indexed: 11/20/2022] Open
Abstract
Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. Its prognosis remains poor, highlighting the need for new therapeutic and precision medicine approaches. AML symptoms often include cytopenias linked to loss of healthy hematopoietic stem and progenitor cells (HSPCs). The mechanisms behind HSPC decline are complex and still poorly understood. Here, intravital microscopy (IVM) of a well-established experimental model of AML allows direct observation of the interactions between healthy and malignant cells in the bone marrow (BM), suggesting that physical dislodgment of healthy cells by AML through damaged vasculature may play an important role. Multiple matrix metalloproteinases (MMPs), known to remodel extracellular matrix, are expressed by AML cells and the BM microenvironment. We reason MMPs could be involved in cell displacement and vascular leakiness; therefore, we evaluate the therapeutic potential of MMP pharmacological inhibition using the broad-spectrum inhibitor prinomastat. IVM analyses of prinomastat-treated mice reveal reduced vascular permeability and healthy cell clusters in circulation and lower AML infiltration, proliferation, and cell migration. Furthermore, treated mice have increased retention of healthy HSPCs in the BM and increased survival following chemotherapy. Analysis of a human AML transcriptomic database reveals widespread MMP deregulation, and human AML cells show susceptibility to MMP inhibition. Overall, our results suggest that MMP inhibition could be a promising complementary therapy to reduce AML growth and limit HSPC loss and BM vascular damage caused by MLL-AF9 and possibly other AML subtypes.
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Affiliation(s)
- Chiara Pirillo
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom
- The Francis Crick Institute, London, United Kingdom
- Beatson Institute for Cancer Research, Glasgow, United Kingdom
| | - Flora Birch
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom
- The Francis Crick Institute, London, United Kingdom
- Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | - Floriane S. Tissot
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom
- The Francis Crick Institute, London, United Kingdom
- Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | - Sara Gonzalez Anton
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom
- The Francis Crick Institute, London, United Kingdom
- Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | - Myriam Haltalli
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom
- The Francis Crick Institute, London, United Kingdom
| | - Valentina Tini
- Institute of Haematology, Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy
| | - Isabella Kong
- The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Parkville, VIC, Australia
| | - Cécile Piot
- The Francis Crick Institute, London, United Kingdom
| | - Ben Partridge
- Department of Bioengineering, Imperial College London, London, United Kingdom
| | - Constandina Pospori
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom
- The Francis Crick Institute, London, United Kingdom
- Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | - Karen Keeshan
- Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | | | - Edwin Hawkins
- The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Parkville, VIC, Australia
| | - Brunangelo Falini
- Institute of Haematology, Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy
| | - Andrea Marra
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom
- Institute of Haematology, Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, Perugia, Italy
| | - Delfim Duarte
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom
- Instituto de Investigação e Inovação em Saúde (i3S) Universidade do Porto, Porto, Portugal
- Department of Onco-Hematology, Instituto Português de Oncologia (IPO), Porto, Portugal; and
- Department of Biomedicine, Unit of Biochemistry, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Chiu Fan Lee
- Department of Bioengineering, Imperial College London, London, United Kingdom
| | - Edward Roberts
- Beatson Institute for Cancer Research, Glasgow, United Kingdom
| | - Cristina Lo Celso
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom
- The Francis Crick Institute, London, United Kingdom
- Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
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21
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Cellular senescence in cancers: relationship between bone marrow cancer and cellular senescence. Mol Biol Rep 2022; 49:4003-4012. [PMID: 35449316 DOI: 10.1007/s11033-021-07101-6] [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: 06/22/2021] [Accepted: 12/16/2021] [Indexed: 10/18/2022]
Abstract
INTRODUCTION There are many factors and conditions that lead to cellular senescence. Replicative senescence and Hayflick phenomenon are the most important causes of cellular senescence. Senescent cells also lead to wound healing conditions resulting from injury and toxic conditions. MATERIAL AND METHODS When a cell becomes senescent, it stops replication and begins to leak inflammatory signals before growth. It also alters the extracellular matrix and behavior of neighbor cells and even motivates them. This review was conducted to determine the association between senescence and bone marrow cancer. RESULTS The results showed that senescent cells have a short life span due to their self-destructive nature or natural removal from the body by the immune system. These signals are effective to a certain extent in regenerating the damaged cells when present in a transient state. Cellular senescence can decrease the risk of all cancers, including bone marrow cancer, ensuring that cells with significant DNA injury are prevented from replication. CONCLUSION However, senescent cells increase in number as they age, which is very harmful over time. These cells extend into an older tissue for longer periods of time and form longer clusters in older tissues. Therefore, cellular senescence significantly contributes to aging.
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22
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Stucky A, Gao L, Li SC, Tu L, Luo J, Huang X, Chen X, Li X, Park TH, Cai J, Kabeer MH, Plant AS, Sun L, Zhang X, Zhong JF. Molecular Characterization of Differentiated-Resistance MSC Subclones by Single-Cell Transcriptomes. Front Cell Dev Biol 2022; 10:699144. [PMID: 35356283 PMCID: PMC8959432 DOI: 10.3389/fcell.2022.699144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 02/14/2022] [Indexed: 11/25/2022] Open
Abstract
Background: The mechanism of tumorigenicity potentially evolved in mesenchymal stem cells (MSCs) remains elusive, resulting in inconsistent clinical application efficacy. We hypothesized that subclones in MSCs contribute to their tumorgenicity, and we approached MSC-subclones at the single-cell level. Methods: MSCs were cultured in an osteogenic differentiation medium and harvested on days 12, 19, and 25 for cell differentiation analysis using Alizarin Red and followed with the single-cell transcriptome. Results: Single-cell RNA-seq analysis reveals a discrete cluster of MSCs during osteogenesis, including differentiation-resistant MSCs (DR-MSCs), differentiated osteoblasts (DO), and precursor osteoblasts (PO). The DR-MSCs population resembled cancer initiation cells and were subjected to further analysis of the yes associated protein 1 (YAP1) network. Verteporfin was also used for YAP1 inhibition in cancer cell lines to confirm the role of YAP1 in MSC--involved tumorigenicity. Clinical data from various cancer types were analyzed to reveal relationships among YAP1, OCT4, and CDH6 in MSC--involved tumorigenicity. The expression of cadherin 6 (CDH6), octamer-binding transcription factor 4 (OCT4), and YAP1 expression was significantly upregulated in DR-MSCs compared to PO and DO. YAP1 inhibition by Verteporfin accelerated the differentiation of MSCs and suppressed the expression of YAP1, CDH6, and OCT4. A survey of 56 clinical cohorts revealed a high degree of co-expression among CDH6, YAP1, and OCT4 in various solid tumors. YAP1 inhibition also down-regulated HeLa cell viability and gradually inhibited YAP1 nuclear localization while reducing the transcription of CDH6 and OCT4. Conclusions: We used single-cell sequencing to analyze undifferentiated MSCs and to discover a carcinogenic pathway in single-cell MSCs of differentiated resistance subclones.
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Affiliation(s)
- Andres Stucky
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, CA, United States
| | - Li Gao
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Shengwen Calvin Li
- Neuro-oncology and Stem Cell Research Laboratory, CHOC Children’s Research Institute, Center for Neuroscience Research, Children’s Hospital of Orange County (CHOC), Orange, CA, United States
- Department of Neurology, Irvine School of Medicine, University of California, Irvine, CA, United States
| | - Lingli Tu
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, CA, United States
- Department of Oncology, Bishan, The People’s Hospital of Bishan District, Bishan, Chongqing, China
| | - Jun Luo
- Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Xi Huang
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xuelian Chen
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, CA, United States
| | - Xiaoqing Li
- Department of Oncology, Bishan, The People’s Hospital of Bishan District, Bishan, Chongqing, China
| | - Tiffany H. Park
- School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Jin Cai
- Department of Oral and Maxillofacial Surgery, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Mustafa H. Kabeer
- Pediatric Surgery, CHOC Children’s Hospital, Department of Surgery, Irvine School of Medicine, University of California, Irvine, CA, United States
| | - Ashley S. Plant
- Division of Pediatric Oncology, Children’s Hospital of Orange County, Orange, CA, United States
| | - Lan Sun
- Department of Oncology, Bishan, The People’s Hospital of Bishan District, Bishan, Chongqing, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Jiang F. Zhong
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, CA, United States
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23
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Venglar O, Bago JR, Motais B, Hajek R, Jelinek T. Natural Killer Cells in the Malignant Niche of Multiple Myeloma. Front Immunol 2022; 12:816499. [PMID: 35087536 PMCID: PMC8787055 DOI: 10.3389/fimmu.2021.816499] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 12/14/2021] [Indexed: 12/12/2022] Open
Abstract
Natural killer (NK) cells represent a subset of CD3- CD7+ CD56+/dim lymphocytes with cytotoxic and suppressor activity against virus-infected cells and cancer cells. The overall potential of NK cells has brought them to the spotlight of targeted immunotherapy in solid and hematological malignancies, including multiple myeloma (MM). Nonetheless, NK cells are subjected to a variety of cancer defense mechanisms, leading to impaired maturation, chemotaxis, target recognition, and killing. This review aims to summarize the available and most current knowledge about cancer-related impairment of NK cell function occurring in MM.
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Affiliation(s)
- Ondrej Venglar
- Faculty of Science, University of Ostrava, Ostrava, Czechia.,Faculty of Medicine, University of Ostrava, Ostrava, Czechia.,Hematooncology Clinic, University Hospital Ostrava, Ostrava, Czechia
| | - Julio Rodriguez Bago
- Faculty of Medicine, University of Ostrava, Ostrava, Czechia.,Hematooncology Clinic, University Hospital Ostrava, Ostrava, Czechia
| | - Benjamin Motais
- Faculty of Science, University of Ostrava, Ostrava, Czechia.,Faculty of Medicine, University of Ostrava, Ostrava, Czechia
| | - Roman Hajek
- Faculty of Medicine, University of Ostrava, Ostrava, Czechia.,Hematooncology Clinic, University Hospital Ostrava, Ostrava, Czechia
| | - Tomas Jelinek
- Faculty of Medicine, University of Ostrava, Ostrava, Czechia.,Hematooncology Clinic, University Hospital Ostrava, Ostrava, Czechia
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24
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Duchmann M, Wagner-Ballon O, Boyer T, Cheok M, Fournier E, Guerin E, Fenwarth L, Badaoui B, Freynet N, Benayoun E, Lusina D, Garcia I, Gardin C, Fenaux P, Pautas C, Quesnel B, Turlure P, Terré C, Thomas X, Lambert J, Renneville A, Preudhomme C, Dombret H, Itzykson R, Cluzeau T. Machine learning identifies the independent role of dysplasia in the prediction of response to chemotherapy in AML. Leukemia 2022; 36:656-663. [PMID: 34615986 DOI: 10.1038/s41375-021-01435-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 09/13/2021] [Accepted: 09/17/2021] [Indexed: 12/17/2022]
Abstract
The independent prognostic impact of specific dysplastic features in acute myeloid leukemia (AML) remains controversial and may vary between genomic subtypes. We apply a machine learning framework to dissect the relative contribution of centrally reviewed dysplastic features and oncogenetics in 190 patients with de novo AML treated in ALFA clinical trials. One hundred and thirty-five (71%) patients achieved complete response after the first induction course (CR). Dysgranulopoiesis, dyserythropoiesis and dysmegakaryopoiesis were assessable in 84%, 83% and 63% patients, respectively. Multi-lineage dysplasia was present in 27% of assessable patients. Micromegakaryocytes (q = 0.01), hypolobulated megakaryocytes (q = 0.08) and hyposegmented granulocytes (q = 0.08) were associated with higher ELN-2017 risk. Using a supervised learning algorithm, the relative importance of morphological variables (34%) for the prediction of CR was higher than demographic (5%), clinical (2%), cytogenetic (25%), molecular (29%), and treatment (5%) variables. Though dysplasias had limited predictive impact on survival, a multivariate logistic regression identified the presence of hypolobulated megakaryocytes (p = 0.014) and micromegakaryocytes (p = 0.035) as predicting lower CR rates, independently of monosomy 7 (p = 0.013), TP53 (p = 0.004), and NPM1 mutations (p = 0.025). Assessment of these specific dysmegakarypoiesis traits, for which we identify a transcriptomic signature, may thus guide treatment allocation in AML.
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Affiliation(s)
- Matthieu Duchmann
- Laboratoire d'Hématologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.,Université de Paris, Génomes, biologie cellulaire et thérapeutique U944, INSERM, CNRS, 75010, Paris, France
| | - Orianne Wagner-Ballon
- Département d'Hématologie et Immunologie biologiques, Hôpital Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France.,INSERM U955 IMRB, UPEC, Créteil, France
| | - Thomas Boyer
- Service d'Hématologie Biologique, CHU Lille, Lille, France.,Service d'Hématologie Biologique, CHU Amiens-Picardie, Amiens, France
| | | | - Elise Fournier
- Service d'Hématologie Biologique, CHU Lille, Lille, France
| | - Estelle Guerin
- Service d'Hématologie biologique, Hôpital Dupuytren, Limoges, France.,UMR CNRS 7276/INSERM 1262, CHU Limoges, Limoges, France
| | - Laurène Fenwarth
- Université Lille, CNRS, INSERM, CHU Lille, IRCL, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000, Lille, France
| | - Bouchra Badaoui
- Département d'Hématologie et Immunologie biologiques, Hôpital Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France
| | - Nicolas Freynet
- Département d'Hématologie et Immunologie biologiques, Hôpital Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France
| | - Emmanuel Benayoun
- Département d'Hématologie et Immunologie biologiques, Hôpital Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France
| | - Daniel Lusina
- Laboratoire d'Hématologie, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Université Sorbonne Paris Cité, Bobigny, France
| | - Isabel Garcia
- Laboratoire d'Hématologie, Hôpital André Mignot, Centre Hospitalier de Versailles, Le Chesnay, France
| | - Claude Gardin
- Département d'Hématologie Clinique, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Bobigny, France
| | - Pierre Fenaux
- Département d'Hématologie Clinique, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
| | - Cécile Pautas
- Département d'Hématologie clinique, Hôpital Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France
| | - Bruno Quesnel
- CHU Lille, Service des Maladies du Sang, 59000, Lille, France
| | - Pascal Turlure
- Département d'Hématologie Clinique, CHU Limoges, Limoges, France
| | - Christine Terré
- Laboratoire de Cytogénétique, Hôpital André Mignot, Centre Hospitalier de Versailles, Le Chesnay, France
| | - Xavier Thomas
- Département d'Hématologie Clinique, Hospices Civils de Lyon, Hôpital Lyon-Sud, Pierre Bénite, France
| | - Juliette Lambert
- Département d'Hématologie Clinique, Hôpital André Mignot, Centre Hospitalier de Versailles, Le Chesnay, France
| | | | - Claude Preudhomme
- Université Lille, CNRS, INSERM, CHU Lille, IRCL, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000, Lille, France
| | - Hervé Dombret
- Département d'Hématologie Clinique, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, EA-3518, Institut de Recherche Saint-Louis, Université de Paris, Paris, France
| | - Raphael Itzykson
- Université de Paris, Génomes, biologie cellulaire et thérapeutique U944, INSERM, CNRS, 75010, Paris, France. .,Département d'Hématologie Clinique, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.
| | - Thomas Cluzeau
- Département d'Hématologie, Université Côte d'Azur, CHU de Nice, Nice, France.
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25
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Ayyadurai VAS, Deonikar P, McLure KG, Sakamoto KM. Molecular Systems Architecture of Interactome in the Acute Myeloid Leukemia Microenvironment. Cancers (Basel) 2022; 14:756. [PMID: 35159023 PMCID: PMC8833542 DOI: 10.3390/cancers14030756] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/29/2022] [Indexed: 12/12/2022] Open
Abstract
A molecular systems architecture is presented for acute myeloid leukemia (AML) to provide a framework for organizing the complexity of biomolecular interactions. AML is a multifactorial disease resulting from impaired differentiation and increased proliferation of hematopoietic precursor cells involving genetic mutations, signaling pathways related to the cancer cell genetics, and molecular interactions between the cancer cell and the tumor microenvironment, including endothelial cells, fibroblasts, myeloid-derived suppressor cells, bone marrow stromal cells, and immune cells (e.g., T-regs, T-helper 1 cells, T-helper 17 cells, T-effector cells, natural killer cells, and dendritic cells). This molecular systems architecture provides a layered understanding of intra- and inter-cellular interactions in the AML cancer cell and the cells in the stromal microenvironment. The molecular systems architecture may be utilized for target identification and the discovery of single and combination therapeutics and strategies to treat AML.
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Affiliation(s)
- V. A. Shiva Ayyadurai
- Systems Biology Group, International Center for Integrative Systems, Cambridge, MA 02138, USA;
| | - Prabhakar Deonikar
- Systems Biology Group, International Center for Integrative Systems, Cambridge, MA 02138, USA;
| | | | - Kathleen M. Sakamoto
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA;
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26
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Cheng AP, Cheng MP, Loy CJ, Lenz JS, Chen K, Smalling S, Burnham P, Timblin KM, Orejas JL, Silverman E, Polak P, Marty FM, Ritz J, De Vlaminck I. Cell-free DNA profiling informs all major complications of hematopoietic cell transplantation. Proc Natl Acad Sci U S A 2022; 119:e2113476118. [PMID: 35058359 PMCID: PMC8795552 DOI: 10.1073/pnas.2113476118] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 11/16/2021] [Indexed: 12/13/2022] Open
Abstract
Allogeneic hematopoietic cell transplantation (HCT) provides effective treatment for hematologic malignancies and immune disorders. Monitoring of posttransplant complications is critical, yet current diagnostic options are limited. Here, we show that cell-free DNA (cfDNA) in blood is a versatile analyte for monitoring of the most important complications that occur after HCT: graft-versus-host disease (GVHD), a frequent immune complication of HCT, infection, relapse of underlying disease, and graft failure. We demonstrate that these therapeutic complications are informed from a single assay, low-coverage bisulfite sequencing of cfDNA, followed by disease-specific bioinformatic analyses. To inform GVHD, we profile cfDNA methylation marks to trace the cfDNA tissues-of-origin and to quantify tissue-specific injury. To inform infection, we implement metagenomic cfDNA profiling. To inform cancer relapse, we implement analyses of tumor-specific genomic aberrations. Finally, to detect graft failure, we quantify the proportion of donor- and recipient-specific cfDNA. We applied this assay to 170 plasma samples collected from 27 HCT recipients at predetermined timepoints before and after allogeneic HCT. We found that the abundance of solid-organ-derived cfDNA in the blood at 1 mo after HCT is predictive of acute GVHD (area under the curve, 0.88). Metagenomic profiling of cfDNA revealed the frequent occurrence of viral reactivation in this patient population. The fraction of donor-specific cfDNA was indicative of relapse and remission, and the fraction of tumor-specific cfDNA was informative of cancer relapse. This proof-of-principle study shows that cfDNA has the potential to improve the care of allogeneic HCT recipients by enabling earlier detection and better prediction of the complex array of complications that occur after HCT.
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Affiliation(s)
| | - Matthew Pellan Cheng
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
- Division of Infectious Disease, Brigham and Women's Hospital, Boston, MA 02215
| | - Conor James Loy
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
| | - Joan Sesing Lenz
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853
| | - Kaiwen Chen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
- Division of Infectious Disease, Brigham and Women's Hospital, Boston, MA 02215
| | - Sami Smalling
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853
| | - Philip Burnham
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104
| | - Kaitlyn Marie Timblin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
- Division of Infectious Disease, Brigham and Women's Hospital, Boston, MA 02215
| | - José Luis Orejas
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
- Division of Infectious Disease, Brigham and Women's Hospital, Boston, MA 02215
| | - Emily Silverman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
- Division of Infectious Disease, Brigham and Women's Hospital, Boston, MA 02215
| | - Paz Polak
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Francisco M Marty
- Division of Infectious Disease, Brigham and Women's Hospital, Boston, MA 02215
- Department of Medicine, Harvard Medical School, Boston, MA 02115
| | - Jerome Ritz
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
- Department of Medicine, Harvard Medical School, Boston, MA 02115
| | - Iwijn De Vlaminck
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853;
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27
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Moore JA, Mistry JJ, Hellmich C, Horton RH, Wojtowicz EE, Jibril A, Jefferson M, Wileman T, Beraza N, Bowles KM, Rushworth SA. LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation. J Clin Invest 2022; 132:153157. [PMID: 34990402 PMCID: PMC8884913 DOI: 10.1172/jci153157] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 12/22/2021] [Indexed: 11/25/2022] Open
Abstract
The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation, and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for remaining apoptotic debris in regulating the immunologic response to and growth of solid tumors. Here, we investigated the role of macrophage LC3–associated phagocytosis (LAP) within the BM microenvironment of AML. Depletion of BM macrophages (BMMs) increased AML growth in vivo. We show that LAP is the predominate method of BMM phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to the accumulation of apoptotic cells (ACs) and apoptotic bodies (ABs), resulting in accelerated leukemia growth. Mechanistically, LAP of AML-derived ABs by BMMs resulted in stimulator of IFN genes (STING) pathway activation. We found that AML-derived mitochondrial damage–associated molecular patterns were processed by BMMs via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML-derived ABs showed that it was this mtDNA that was responsible for the induction of STING signaling in BMMs. Phenotypically, we found that STING activation suppressed AML growth through a mechanism related to increased phagocytosis. In summary, we report that macrophage LAP of apoptotic debris in the AML BM microenvironment suppressed tumor growth.
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Affiliation(s)
- Jamie A Moore
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Jayna J Mistry
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Charlotte Hellmich
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Rebecca H Horton
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | | | - Aisha Jibril
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Matthew Jefferson
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Thomas Wileman
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Naiara Beraza
- Quadram Institute Biosciences, Norwich, United Kingdom
| | - Kristian M Bowles
- Department of Haematology, Norwich Medical School, Norwich, United Kingdom
| | - Stuart A Rushworth
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom
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28
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Torquato HFV, Junior MTR, Lima CS, Júnior RTDA, Talhati F, Dias DA, Justo GZ, Ferreira AT, Pilli RA, Paredes-Gamero EJ. A canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with DNA damage in acute myeloid cells. Biomed Pharmacother 2022; 145:112439. [PMID: 34808555 DOI: 10.1016/j.biopha.2021.112439] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/10/2021] [Accepted: 11/12/2021] [Indexed: 02/07/2023] Open
Abstract
Natural products have long been considered a relevant source of new antitumor agents. Despite advances in the treatment of younger patients with acute myeloid leukemia (AML), the prognosis of elderly patients remains poor, with a high frequency of relapse. The cytotoxicity of canthin-6-one alkaloids has been extensively studied in different cell types, including leukemic strains. Among the canthin-6-one analogs tested, 10-methoxycanthin-6-one (Mtx-C) showed the highest cytotoxicity in the malignant AML cells Kasumi-1 and KG-1. Thus, we evaluated the cytotoxicity and cell death mechanisms related to Mtx-C using the EC50 (80 µM for Kasumi-1 and 36 µM for KG-1) treatment for 24 h. Our results identify reactive oxygen species production, mitochondrial depolarization, annexin V-FITC/7-AAD double staining, caspase cleave and upregulation of mitochondria-dependent apoptosis proteins (Bax, Bim, Bik, Puma and phosphorylation of p53) for both cell lineages. However, downregulation of Bcl-2 and the simultaneous execution of the apoptotic and necroptotic programs associated with the phosphorylation of the proteins receptor-interacting serine/threonine-protein kinase 3 and mixed lineage kinase domain-like pseudokinase occurred only in Kasumi-1 cells. About the lasted events, Kasumi-1 cell death was inhibited by pharmacological agents such as Zvad-FMK and necrostatin-1. The underlying molecular mechanisms of Mtx-C still include participation in the DNA damage and stress-signaling pathways involving p38 and c-Jun N-terminal mitogen-activated protein kinases and interaction with DNA. Thus, Mtx-C represents a promising tool for the development of new antileukemic molecules.
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Affiliation(s)
- Heron F V Torquato
- Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, 04044-020 São Paulo, SP, Brazil; Faculdade de Farmácia, Centro Universitário Braz Cubas, 08773-380 Mogi das Cruzes, SP, Brazil; Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grosso do Sul, 79070-900 Campo Grande, MS, Brazil
| | | | - Cauê Santos Lima
- Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, 04044-020 São Paulo, SP, Brazil
| | - Roberto Theodoro de Araujo Júnior
- Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, 04044-020 São Paulo, SP, Brazil; Faculdade de Farmácia, Centro Universitário Braz Cubas, 08773-380 Mogi das Cruzes, SP, Brazil
| | - Fernanda Talhati
- Faculdade de Farmácia, Centro Universitário Braz Cubas, 08773-380 Mogi das Cruzes, SP, Brazil
| | - Dhebora Albuquerque Dias
- Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grosso do Sul, 79070-900 Campo Grande, MS, Brazil
| | - Giselle Zenker Justo
- Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, 04044-020 São Paulo, SP, Brazil
| | - Alice Teixeira Ferreira
- Departamento de Biofísica, Universidade Federal de São Paulo, R. Três de Maio 100, 04044-020 São Paulo, SP, Brazil
| | - Ronaldo Aloise Pilli
- Instituto de Química, Universidade Estadual de Campinas, 13084-971 Campinas, SP, Brazil
| | - Edgar J Paredes-Gamero
- Departamento de Bioquímica, Universidade Federal de São Paulo, R. Três de Maio 100, 04044-020 São Paulo, SP, Brazil; Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grosso do Sul, 79070-900 Campo Grande, MS, Brazil.
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29
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Ganesan S, Mathews V, Vyas N. Microenvironment and drug resistance in acute myeloid leukemia: Do we know enough? Int J Cancer 2021; 150:1401-1411. [PMID: 34921734 DOI: 10.1002/ijc.33908] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 12/18/2022]
Abstract
Acute myeloid leukemia (AMLs), as the name suggests, often develop suddenly and are very progressive forms of cancer. Unlike in acute promyelocytic leukemia, a subtype of AML, the outcomes in most other AMLs remain poor. This is mainly attributed to the acquired drug resistance and lack of targeted therapy. Different studies across laboratories suggest that the cellular mechanisms to impart therapy resistance are often very dynamic and should be identified in a context-specific manner. Our review highlights the progress made so far in identifying the different cellular mechanisms of mutation-independent therapy resistance in AML. It reiterates that for more effective outcomes cancer therapies should acquire a more tailored approach where the protective interactions between the cancer cells and their niches are identified and targeted.
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Affiliation(s)
- Saravanan Ganesan
- Department of Haematology, Christian Medical College, Vellore, India
| | - Vikram Mathews
- Department of Haematology, Christian Medical College, Vellore, India
| | - Neha Vyas
- Division of Molecular Medicine, St. John's Research Institute, SJNAHS, Bengaluru, India
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30
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Bolandi SM, Pakjoo M, Beigi P, Kiani M, Allahgholipour A, Goudarzi N, Khorashad JS, Eiring AM. A Role for the Bone Marrow Microenvironment in Drug Resistance of Acute Myeloid Leukemia. Cells 2021; 10:2833. [PMID: 34831055 PMCID: PMC8616250 DOI: 10.3390/cells10112833] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 02/08/2023] Open
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease with a poor prognosis and remarkable resistance to chemotherapeutic agents. Understanding resistance mechanisms against currently available drugs helps to recognize the therapeutic obstacles. Various mechanisms of resistance to chemotherapy or targeted inhibitors have been described for AML cells, including a role for the bone marrow niche in both the initiation and persistence of the disease, and in drug resistance of the leukemic stem cell (LSC) population. The BM niche supports LSC survival through direct and indirect interactions among the stromal cells, hematopoietic stem/progenitor cells, and leukemic cells. Additionally, the BM niche mediates changes in metabolic and signal pathway activation due to the acquisition of new mutations or selection and expansion of a minor clone. This review briefly discusses the role of the BM microenvironment and metabolic pathways in resistance to therapy, as discovered through AML clinical studies or cell line and animal models.
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Affiliation(s)
- Seyed Mohammadreza Bolandi
- Department of Immunology, Razi Vaccine and Sera Research Institute, Karaj, Iran; (S.M.B.); (N.G.)
- Department of Pharmacology, Karaj Branch, Islamic Azad University, Karaj, Iran; (M.K.); (A.A.)
| | - Mahdi Pakjoo
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; (M.P.); (P.B.)
| | - Peyman Beigi
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; (M.P.); (P.B.)
| | - Mohammad Kiani
- Department of Pharmacology, Karaj Branch, Islamic Azad University, Karaj, Iran; (M.K.); (A.A.)
| | - Ali Allahgholipour
- Department of Pharmacology, Karaj Branch, Islamic Azad University, Karaj, Iran; (M.K.); (A.A.)
| | - Negar Goudarzi
- Department of Immunology, Razi Vaccine and Sera Research Institute, Karaj, Iran; (S.M.B.); (N.G.)
| | - Jamshid S. Khorashad
- Centre for Haematology, Hammersmith Hospital, Imperial College London, London W12 0HS, UK;
| | - Anna M. Eiring
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX 79905, USA
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31
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Tawfik EA, Aldrak NA, Albrahim SH, Alzahrani DA, Alfassam HA, Alkoblan SM, Almalik AM, Chen KS, Abou-Khalil R, Shah K, Zaidan NM. Immunotherapy in hematological malignancies: recent advances and open questions. Immunotherapy 2021; 13:1215-1229. [PMID: 34498496 DOI: 10.2217/imt-2021-0065] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Over recent years, tremendous advances in immunotherapy approaches have been observed, generating significant clinical progress. Cancer immunotherapy has been shown, in different types of blood cancers, to improve the overall survival of patients. Immunotherapy treatment of hematopoietic malignancies is a newly growing field that has been accelerating over the past years. Several US FDA approved drugs and cell-based therapies are being exploited in the late stage of clinical trials. This review attempt to highlight and discuss the numerous innovative immunotherapy approaches of hematopoietic malignancy ranging from nonmyeloablative transplantation, T-cell immunotherapy, natural killer cells and immune agonist to monoclonal antibodies and vaccination. In addition, a brief discussion on the future advances and accomplishments required to counterpart the current immunotherapeutic approaches for hematopoietic malignancies were also highlighted.
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Affiliation(s)
- Essam A Tawfik
- Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science & Technology (KACST), PO Box 6086, Riyadh, 11442, Saudi Arabia.,National Center for Pharmaceutical Technology, Life Science & Environment Research Institute, King Abdulaziz City for Science & Technology (KACST), PO Box 6086, Riyadh, 11442, Saudi Arabia
| | - Norah A Aldrak
- Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science & Technology (KACST), PO Box 6086, Riyadh, 11442, Saudi Arabia
| | - Shahad H Albrahim
- Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science & Technology (KACST), PO Box 6086, Riyadh, 11442, Saudi Arabia
| | - Dunia A Alzahrani
- National Center for Pharmaceutical Technology, Life Science & Environment Research Institute, King Abdulaziz City for Science & Technology (KACST), PO Box 6086, Riyadh, 11442, Saudi Arabia
| | - Haya A Alfassam
- Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science & Technology (KACST), PO Box 6086, Riyadh, 11442, Saudi Arabia
| | - Samar M Alkoblan
- Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science & Technology (KACST), PO Box 6086, Riyadh, 11442, Saudi Arabia
| | - Abdulaziz M Almalik
- Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science & Technology (KACST), PO Box 6086, Riyadh, 11442, Saudi Arabia.,National Center for Pharmaceutical Technology, Life Science & Environment Research Institute, King Abdulaziz City for Science & Technology (KACST), PO Box 6086, Riyadh, 11442, Saudi Arabia
| | - Kok-Siong Chen
- BWH Center of Excellence for Biomedicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Center for Stem Cell Therapeutics & Imaging, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Rana Abou-Khalil
- Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science & Technology (KACST), PO Box 6086, Riyadh, 11442, Saudi Arabia
| | - Khalid Shah
- BWH Center of Excellence for Biomedicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Center for Stem Cell Therapeutics & Imaging, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Nada M Zaidan
- Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science & Technology (KACST), PO Box 6086, Riyadh, 11442, Saudi Arabia
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32
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Namburi S, Broxmeyer HE, Hong CS, Whiteside TL, Boyiadzis M. DPP4 + exosomes in AML patients' plasma suppress proliferation of hematopoietic progenitor cells. Leukemia 2021; 35:1925-1932. [PMID: 33139859 PMCID: PMC10165724 DOI: 10.1038/s41375-020-01047-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 08/07/2020] [Accepted: 09/29/2020] [Indexed: 02/04/2023]
Abstract
Mechanisms by which acute myeloid leukemia (AML) interferes with normal hematopoiesis are under intense investigation. Emerging evidence suggests that exosomes produced by leukemia blasts suppress hematopoiesis. Exosomes isolated from AML patients' plasma at diagnosis significantly and dose-dependently suppressed colony formation of normal hematopoietic progenitor cells (HPC). Levels of HPC suppression mediated by exosomes of AML patients who achieved complete remission (CR) were significantly decreased compared to those observed at AML diagnosis. Exosomes from plasma of patients who had achieved CR but with incomplete cell count recovery (CRi) after chemotherapy suppressed in vitro colony formation as effectively as did exosomes obtained at AML diagnosis. Dipeptidylpeptidase4 (DPP4/CD26), a serine protease that cleaves select penultimate amino acids of various proteins, has been previously implicated in the regulation of hematopoiesis. DPP4 was carried by exosomes from AML plasma or leukemia cell lines. Leukemia exosomes which suppressed HSC colony formation had markedly higher DPP4 functional activity than that detected in the exosomes of normal donors. Pharmacological inhibition of DPP4 activity in AML exosomes reversed the effects of exosome-mediated myelosuppression. Reversing the negative effects of exosomes on AML hematopoiesis, and thus improving cell count recovery, might emerge as a new therapeutic approach to AML.
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Affiliation(s)
- Swathi Namburi
- University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Hal E Broxmeyer
- Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chang-Sook Hong
- University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Theresa L Whiteside
- University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Michael Boyiadzis
- University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
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33
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Zhang TY, Dutta R, Benard B, Zhao F, Yin R, Majeti R. IL-6 blockade reverses bone marrow failure induced by human acute myeloid leukemia. Sci Transl Med 2021; 12:12/538/eaax5104. [PMID: 32269167 DOI: 10.1126/scitranslmed.aax5104] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 12/04/2019] [Accepted: 01/31/2020] [Indexed: 12/18/2022]
Abstract
Most patients with acute myeloid leukemia (AML) die from complications arising from cytopenias resulting from bone marrow (BM) failure. The common presumption among physicians is that AML-induced BM failure is primarily due to overcrowding, yet BM failure is observed even with low burden of disease. Here, we use large clinical datasets to show the lack of correlation between BM blast burden and degree of cytopenias at the time of diagnosis. We develop a splenectomized xenograft model to demonstrate that transplantation of human primary AML into immunocompromised mice recapitulates the human disease course by induction of BM failure via depletion of mouse hematopoietic stem and progenitor populations. Using unbiased approaches, we show that AML-elaborated IL-6 acts to block erythroid differentiation at the proerythroblast stage and that blocking antibodies against human IL-6 can improve AML-induced anemia and prolong overall survival, suggesting a potential therapeutic approach.
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Affiliation(s)
- Tian Yi Zhang
- Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.,Stanford School of Medicine, Stanford, CA 94305, USA.,Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA
| | - Ritika Dutta
- Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.,Stanford School of Medicine, Stanford, CA 94305, USA
| | - Brooks Benard
- Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Feifei Zhao
- Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.,Stanford School of Medicine, Stanford, CA 94305, USA.,Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA
| | - Raymond Yin
- Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.,Stanford School of Medicine, Stanford, CA 94305, USA.,Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA
| | - Ravindra Majeti
- Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA. .,Stanford School of Medicine, Stanford, CA 94305, USA.,Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA
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34
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Jäger P, Geyh S, Twarock S, Cadeddu RP, Rabes P, Koch A, Maus U, Hesper T, Zilkens C, Rautenberg C, Bormann F, Köhrer K, Petzsch P, Wieczorek D, Betz B, Surowy H, Hildebrandt B, Germing U, Kobbe G, Haas R, Schroeder T. Acute myeloid leukemia-induced functional inhibition of healthy CD34+ hematopoietic stem and progenitor cells. STEM CELLS (DAYTON, OHIO) 2021; 39:1270-1284. [PMID: 34013984 DOI: 10.1002/stem.3387] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 03/01/2021] [Accepted: 03/21/2021] [Indexed: 11/11/2022]
Abstract
Acute myeloid leukemia (AML) is characterized by an expansion of leukemic cells and a simultaneous reduction of normal hematopoietic precursors in the bone marrow (BM) resulting in hematopoietic insufficiency, but the underlying mechanisms are poorly understood in humans. Assuming that leukemic cells functionally inhibit healthy CD34+ hematopoietic stem and progenitor cells (HSPC) via humoral factors, we exposed healthy BM-derived CD34+ HSPC to cell-free supernatants derived from AML cell lines as well as from 24 newly diagnosed AML patients. Exposure to AML-derived supernatants significantly inhibited proliferation, cell cycling, colony formation, and differentiation of healthy CD34+ HSPC. RNA sequencing of healthy CD34+ HSPC after exposure to leukemic conditions revealed a specific signature of genes related to proliferation, cell-cycle regulation, and differentiation, thereby reflecting their functional inhibition on a molecular level. Experiments with paired patient samples showed that these inhibitory effects are markedly related to the immunomagnetically enriched CD34+ leukemic cell population. Using PCR, ELISA, and RNA sequencing, we detected overexpression of TGFβ1 in leukemic cells on the transcriptional and protein level and, correspondingly, a molecular signature related to TGFβ1 signaling in healthy CD34+ HSPC. This inhibitory effect of TGFβ1 on healthy hematopoiesis was functionally corrobated and could be pharmacologically reverted by SD208, an inhibitor of TGFβ receptor 1 signaling. Overall, these data indicate that leukemic cells induce functional inhibition of healthy CD34+ HSPC, at least in part, through TGFβ1, suggesting that blockage of this pathway may improve hematopoiesis in AML.
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Affiliation(s)
- Paul Jäger
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Stefanie Geyh
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Sören Twarock
- Institute of Pharmacology and Clinical Pharmacology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Ron-Patrick Cadeddu
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Pablo Rabes
- Institute of Pharmacology and Clinical Pharmacology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Annemarie Koch
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Uwe Maus
- Department of Orthopaedies and Hand Surgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Tobias Hesper
- Department of Orthopaedies and Hand Surgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Christoph Zilkens
- Department of Orthopaedies and Hand Surgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Christina Rautenberg
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | | | - Karl Köhrer
- Biological and Medical Research Center (BMFZ), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Patrick Petzsch
- Biological and Medical Research Center (BMFZ), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Dagmar Wieczorek
- Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Beate Betz
- Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Harald Surowy
- Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Barbara Hildebrandt
- Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Ulrich Germing
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Guido Kobbe
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Rainer Haas
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Thomas Schroeder
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
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35
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Acute Myeloid Leukemia: Is It T Time? Cancers (Basel) 2021; 13:cancers13102385. [PMID: 34069204 PMCID: PMC8156992 DOI: 10.3390/cancers13102385] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/30/2021] [Accepted: 05/10/2021] [Indexed: 12/24/2022] Open
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease driven by impaired differentiation of hematopoietic primitive cells toward myeloid lineages (monocytes, granulocytes, red blood cells, platelets), leading to expansion and accumulation of "stem" and/or "progenitor"-like or differentiated leukemic cells in the bone marrow and blood. AML progression alters the bone marrow microenvironment and inhibits hematopoiesis' proper functioning, causing sustained cytopenia and immunodeficiency. This review describes how the AML microenvironment influences lymphoid lineages, particularly T lymphocytes that originate from the thymus and orchestrate adaptive immune response. We focus on the elderly population, which is mainly affected by this pathology. We discuss how a permissive AML microenvironment can alter and even worsen the thymic function, T cells' peripheral homeostasis, phenotype, and functions. Based on the recent findings on the mechanisms supporting that AML induces quantitative and qualitative changes in T cells, we suggest and summarize current immunotherapeutic strategies and challenges to overcome these anomalies to improve the anti-leukemic immune response and the clinical outcome of patients.
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36
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Guo R, Lü M, Cao F, Wu G, Gao F, Pang H, Li Y, Zhang Y, Xing H, Liang C, Lyu T, Du C, Li Y, Guo R, Xie X, Li W, Liu D, Song Y, Jiang Z. Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment. Biomark Res 2021; 9:15. [PMID: 33648605 PMCID: PMC7919996 DOI: 10.1186/s40364-021-00265-0] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 02/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Knowledge of immune cell phenotypes, function, and developmental trajectory in acute myeloid leukemia (AML) microenvironment is essential for understanding mechanisms of evading immune surveillance and immunotherapy response of targeting special microenvironment components. METHODS Using a single-cell RNA sequencing (scRNA-seq) dataset, we analyzed the immune cell phenotypes, function, and developmental trajectory of bone marrow (BM) samples from 16 AML patients and 4 healthy donors, but not AML blasts. RESULTS We observed a significant difference between normal and AML BM immune cells. Here, we defined the diversity of dendritic cells (DC) and macrophages in different AML patients. We also identified several unique immune cell types including T helper cell 17 (TH17)-like intermediate population, cytotoxic CD4+ T subset, T cell: erythrocyte complexes, activated regulatory T cells (Treg), and CD8+ memory-like subset. Emerging AML cells remodels the BM immune microenvironment powerfully, leads to immunosuppression by accumulating exhausted/dysfunctional immune effectors, expending immune-activated types, and promoting the formation of suppressive subsets. CONCLUSION Our results provide a comprehensive AML BM immune cell census, which can help to select pinpoint targeted drug and predict efficacy of immunotherapy.
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Affiliation(s)
- Rongqun Guo
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mengdie Lü
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng, Henan, China
| | - Fujiao Cao
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Guanghua Wu
- The Academy of Medical Science, College of Medical, Zhengzhou University, Zhengzhou, Henan, China
| | - Fengcai Gao
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Haili Pang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yadan Li
- The Academy of Medical Science, College of Medical, Zhengzhou University, Zhengzhou, Henan, China
- The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Yinyin Zhang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Haizhou Xing
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Chunyan Liang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Tianxin Lyu
- The Academy of Medical Science, College of Medical, Zhengzhou University, Zhengzhou, Henan, China
- The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Chunyan Du
- Laboratory Animal Center, School of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Yingmei Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Rong Guo
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xinsheng Xie
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Wei Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Delong Liu
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Yongping Song
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Zhongxing Jiang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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37
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Yamaguchi T, Kawamoto E, Gaowa A, Park EJ, Shimaoka M. Remodeling of Bone Marrow Niches and Roles of Exosomes in Leukemia. Int J Mol Sci 2021; 22:ijms22041881. [PMID: 33668652 PMCID: PMC7918833 DOI: 10.3390/ijms22041881] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/23/2021] [Accepted: 02/11/2021] [Indexed: 12/15/2022] Open
Abstract
Leukemia is a hematological malignancy that originates from hematopoietic stem cells in the bone marrow. Significant progress has made in understanding its pathogensis and in establishing chemotherapy and hematopoietic stem cell transplantation therapy (HSCT). However, while the successive development of new therapies, such as molecular-targeted therapy and immunotherapy, have resulted in remarkable advances, the fact remains that some patients still cannot be saved, and resistance to treatment and relapse are still problems that need to be solved in leukemia patients. The bone marrow (BM) niche is a microenvironment that includes hematopoietic stem cells and their supporting cells. Leukemia cells interact with bone marrow niches and modulate them, not only inducing molecular and functional changes but also switching to niches favored by leukemia cells. The latter are closely associated with leukemia progression, suppression of normal hematopoiesis, and chemotherapy resistance, which is precisely the area of ongoing study. Exosomes play an important role in cell-to-cell communication, not only with cells in close proximity but also with those more distant due to the nature of exosomal circulation via body fluids. In leukemia, exosomes play important roles in leukemogenesis, disease progression, and organ invasion, and their usefulness in the diagnosis and treatment of leukemia has recently been reported. The interaction between leukemia cell-derived exosomes and the BM microenvironment has received particular attention. Their interaction is believed to play a very important role; in addition to their diagnostic value, exosomes could serve as a marker for monitoring treatment efficacy and as an aid in overcoming drug resistance, among the many problems in leukemia patients that have yet to be overcome. In this paper, we will review bone marrow niches in leukemia, findings on leukemia-derived exosomes, and exosome-induced changes in bone marrow niches.
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Affiliation(s)
- Takanori Yamaguchi
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-City, Mie 514-8507, Japan; (T.Y.); (E.K.); (A.G.); (E.J.P.)
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-City, Mie 514-8507, Japan
| | - Eiji Kawamoto
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-City, Mie 514-8507, Japan; (T.Y.); (E.K.); (A.G.); (E.J.P.)
- Department of Emergency and Disaster Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-City, Mie 514-8507, Japan
| | - Arong Gaowa
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-City, Mie 514-8507, Japan; (T.Y.); (E.K.); (A.G.); (E.J.P.)
| | - Eun Jeong Park
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-City, Mie 514-8507, Japan; (T.Y.); (E.K.); (A.G.); (E.J.P.)
| | - Motomu Shimaoka
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-City, Mie 514-8507, Japan; (T.Y.); (E.K.); (A.G.); (E.J.P.)
- Correspondence: ; Tel.: +81-59-232-5036; Fax: +81-59-231-5209
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38
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Understanding of the crosstalk between normal residual hematopoietic stem cells and the leukemic niche in acute myeloid leukemia. Exp Hematol 2021; 95:23-30. [PMID: 33497761 DOI: 10.1016/j.exphem.2021.01.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/29/2020] [Accepted: 01/21/2021] [Indexed: 12/16/2022]
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease, yet clinically most patients present with pancytopenia resulting from bone marrow failure, predisposing them to life-threatening infections and bleeding. The mechanisms by which AML mediates hematopoietic suppression is not well known. Indeed, much effort has so far been focused on how AML remodels the bone marrow niche to make it a more permissive environment, with less focus on how the remodeled niche affects normal hematopoietic cells. In this perspective, we present evidence of the key role of the bone marrow niche in suppressing hematopoietic stem cells (HSCs) during leukemic progression and provide perspectives on how future research on this topic may be exploited to provide treatments for one of the key complications of AML.
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39
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Miao R, Lim VY, Kothapalli N, Ma Y, Fossati J, Zehentmeier S, Sun R, Pereira JP. Hematopoietic Stem Cell Niches and Signals Controlling Immune Cell Development and Maintenance of Immunological Memory. Front Immunol 2020; 11:600127. [PMID: 33324418 PMCID: PMC7726109 DOI: 10.3389/fimmu.2020.600127] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 10/29/2020] [Indexed: 12/11/2022] Open
Abstract
Studies over the last couple of decades have shown that hematopoietic stem cells (HSCs) are critically dependent on cytokines such as Stem Cell Factor and other signals provided by bone marrow niches comprising of mesenchymal stem and progenitor cells (MSPCs) and endothelial cells (ECs). Because of their critical roles in HSC maintenance the niches formed by MSPCs and ECs are commonly referred to as HSC niches. For the most part, the signals required for HSC maintenance act in a short-range manner, which imposes the necessity for directional and positional cues in order for HSCs to localize and be retained properly in stem cell niches. The chemokine CXCL12 and its Gαi protein coupled receptor CXCR4, besides promoting HSC quiescence directly, also play instrumental roles in enabling HSCs to access bone marrow stem cell niches. Recent studies have revealed, however, that HSC niches also provide a constellation of hematopoietic cytokines that are critical for the production of most, if not all, blood cell types. Some hematopoietic cytokines, namely IL-7 and IL-15 produced by HSC niches, are not only required for lymphopoiesis but are also essential for memory T cell maintenance. Consequently, hematopoietic progenitors and differentiated immune cells, such as memory T cell subsets, also depend on the CXCL12/CXCR4 axis for migration into bone marrow and interactions with MSPCs and ECs. Similarly, subsets of antibody-secreting plasma cells also reside in close association with CXCL12-producing MSPCs in the bone marrow and require the CXCR4/CXCL12 axis for survival and long-term maintenance. Collectively, these studies demonstrate a broad range of key physiological roles, spanning blood cell production and maintenance of immunological memory, that are orchestrated by stem cell niches through a common and simple mechanism: CXCL12/CXCR4-mediated cell recruitment followed by receipt of a maintenance and/or instructive signal. A fundamental flaw of this type of cellular organization is revealed by myeloid and lymphoid leukemias, which target stem cell niches and induce profound transcriptomic changes that result in reduced hematopoietic activity and altered mesenchymal cell differentiation.
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Affiliation(s)
- Runfeng Miao
- Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, United States
| | - Vivian Y Lim
- Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, United States
| | - Neeharika Kothapalli
- Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, United States
| | - Yifan Ma
- Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, United States
| | - Julia Fossati
- Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, United States
| | - Sandra Zehentmeier
- Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, United States
| | - Ruifeng Sun
- Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, United States
| | - João P Pereira
- Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, United States
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40
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Hoffmann H, Thiede C, Glauche I, Bornhaeuser M, Roeder I. Differential response to cytotoxic therapy explains treatment dynamics of acute myeloid leukaemia patients: insights from a mathematical modelling approach. J R Soc Interface 2020; 17:20200091. [PMID: 32900301 DOI: 10.1098/rsif.2020.0091] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Disease response and durability of remission are very heterogeneous in patients with acute myeloid leukaemia (AML). There is increasing evidence that the individual risk of early relapse can be predicted based on the initial treatment response. However, it is unclear how such a correlation is linked to functional aspects of AML progression and treatment. We suggest a mathematical model in which leukaemia-initiating cells and normal/healthy haematopoietic stem and progenitor cells reversibly change between an active state characterized by proliferation and chemosensitivity and a quiescent state, in which the cells do not divide, but are also insensitive to chemotherapy. Applying this model to 275 molecular time courses of nucleophosmin 1-mutated patients, we conclude that the differential chemosensitivity of the leukaemia-initiating cells together with the cells' intrinsic proliferative capacity is sufficient to reproduce both, early relapse as well as long-lasting remission. We can, furthermore, show that the model parameters associated with individual chemosensitivity and proliferative advantage of the leukaemic cells are closely linked to the patients' time to relapse, while a reliable prediction based on early response only is not possible based on the currently available data. Although we demonstrate with our approach, that the complete response data is sufficient to quantify the aggressiveness of the disease, further investigations are necessary to study how an intensive early sampling strategy may prospectively improve risk assessment and help to optimize individual treatments.
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Affiliation(s)
- H Hoffmann
- Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden, Germany
| | - C Thiede
- Medical Clinic and Polyclinic I, University Hospital Dresden Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - I Glauche
- Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden, Germany
| | - M Bornhaeuser
- Medical Clinic and Polyclinic I, University Hospital Dresden Carl Gustav Carus, TU Dresden, Dresden, Germany.,National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
| | - I Roeder
- Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden, Germany.,National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
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41
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Wang Y, Wang H, Wang W, Liu W, Liu N, Liu S, Lu Y. Prognostic value of platelet recovery degree before and after achieving minimal residual disease negative complete remission in acute myeloid leukemia patients. BMC Cancer 2020; 20:732. [PMID: 32758189 PMCID: PMC7409648 DOI: 10.1186/s12885-020-07222-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 07/27/2020] [Indexed: 12/19/2022] Open
Abstract
Background Risk stratification and prognosis prediction of acute myeloid leukemia (AML) are largely dependent on pre-treatment information. However, post-treatment data also provides much useful information. In this retrospective study, we explored whether the level of blood count recovery before and after the first minimal residual disease (MRD) negative complete remission (CR) is relevant to clinical outcomes of AML patients. Methods For each included patient, peripheral platelet counts were measured on the day before initial treatment (PLTpre), whereas platelet peak values (PLTpeak) were recorded after marrow recovery following the chemotherapy course inducing the first MRD-negative CR. The difference (DPLT) between these two values (DPLT = PLTpeak−PLTpre) was calculated. X-tile software was utilized to establish the optimal cut-point for DPLT, which was expected to distinguish CR patients with different clinical outcomes. A cross validation analysis was conducted to confirm the robustness of the established cut-point. The results were further tested by a Cox multivariate analysis. Results The optimal cut-point of DPLT was determined as 212 × 109/L. Patients in high DPLT group were observed to have a significantly better PFS (p = 0.016) and a better OS (without statistical significance, p = 0.106). Cox multivariate analysis showed that higher DPLT was associated with longer PFS (HR = 2.894, 95% CI: 1.320–6.345, p = 0.008) and longer OS (HR = 3.077, 95% CI: 1.130–8.376, p = 0.028). Conclusion Platelet recovery degree before and after achieving MRD-negative CR (DPLT) is a potential predictor of clinical outcomes in CR patients. Higher DPLT value is associated with longer PFS and OS. Our findings may help to develop simple methods for AML prognosis evaluation.
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Affiliation(s)
- Yang Wang
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, 651 Dongfengdong Rd, Guangzhou, 510060, China.,State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Hua Wang
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, 651 Dongfengdong Rd, Guangzhou, 510060, China.,State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Weida Wang
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, 651 Dongfengdong Rd, Guangzhou, 510060, China.,State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Wenjian Liu
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, 651 Dongfengdong Rd, Guangzhou, 510060, China.,State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Nawei Liu
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, 651 Dongfengdong Rd, Guangzhou, 510060, China.,State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Shuang Liu
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, 651 Dongfengdong Rd, Guangzhou, 510060, China.,State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Yue Lu
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, 651 Dongfengdong Rd, Guangzhou, 510060, China. .,State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
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42
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Highly multiplexed proteomic assessment of human bone marrow in acute myeloid leukemia. Blood Adv 2020; 4:367-379. [PMID: 31985806 DOI: 10.1182/bloodadvances.2019001124] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 12/16/2019] [Indexed: 02/07/2023] Open
Abstract
Acute myeloid leukemia (AML) is a genetically heterogeneous disease that is characterized by abnormal clonal proliferation of myeloid progenitor cells found predominantly within the bone marrow (BM) and blood. Recent studies suggest that genetic and phenotypic alterations in the BM microenvironment support leukemogenesis and allow leukemic cells to survive and evade chemotherapy-induced death. However, despite substantial evidence indicating the role of tumor-host interactions in AML pathogenesis, little is known about the complex microenvironment of the BM. To address this, we performed novel proteomic profiling of the noncellular compartment of the BM microenvironment in patients with AML (n = 10) and age- and sex-matched healthy control subjects (n = 10) using an aptamer-based, highly multiplexed, affinity proteomics platform (SOMAscan). We show that proteomic assessment of blood or RNA-sequencing of BM are suboptimal alternate screening strategies to determine the true proteomic composition of the extracellular soluble compartment of AML patient BM. Proteomic analysis revealed that 168 proteins significantly differed in abundance, with 91 upregulated and 77 downregulated in leukemic BM. A highly connected signaling network of cytokines and chemokines, including IL-8, was found to be the most prominent proteomic signature associated with AML in the BM microenvironment. We report the first description of significantly elevated levels of the myelosuppressive chemokine CCL23 (myeloid progenitor inhibitory factor-1) in both AML and myelodysplastic syndrome patients and perform functional experiments supportive of a role in the suppression of normal hematopoiesis. This unique paired RNA-sequencing and proteomics data set provides innovative mechanistic insights into AML and healthy aging and should serve as a useful public resource.
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43
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Waclawiczek A, Hamilton A, Rouault-Pierre K, Abarrategi A, Albornoz MG, Miraki-Moud F, Bah N, Gribben J, Fitzgibbon J, Taussig D, Bonnet D. Mesenchymal niche remodeling impairs hematopoiesis via stanniocalcin 1 in acute myeloid leukemia. J Clin Invest 2020; 130:3038-3050. [PMID: 32364536 PMCID: PMC7260026 DOI: 10.1172/jci133187] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 02/26/2020] [Indexed: 12/12/2022] Open
Abstract
Acute myeloid leukemia (AML) disrupts the generation of normal blood cells, predisposing patients to hemorrhage, anemia, and infections. Differentiation and proliferation of residual normal hematopoietic stem and progenitor cells (HSPCs) are impeded in AML-infiltrated bone marrow (BM). The underlying mechanisms and interactions of residual hematopoietic stem cells (HSCs) within the leukemic niche are poorly understood, especially in the human context. To mimic AML infiltration and dissect the cellular crosstalk in human BM, we established humanized ex vivo and in vivo niche models comprising AML cells, normal HSPCs, and mesenchymal stromal cells (MSCs). Both models replicated the suppression of phenotypically defined HSPC differentiation without affecting their viability. As occurs in AML patients, the majority of HSPCs were quiescent and showed enrichment of functional HSCs. HSPC suppression was largely dependent on secreted factors produced by transcriptionally remodeled MSCs. Secretome analysis and functional validation revealed MSC-derived stanniocalcin 1 (STC1) and its transcriptional regulator HIF-1α as limiting factors for HSPC proliferation. Abrogation of either STC1 or HIF-1α alleviated HSPC suppression by AML. This study provides a humanized model to study the crosstalk among HSPCs, leukemia, and their MSC niche, and a molecular mechanism whereby AML impairs normal hematopoiesis by remodeling the mesenchymal niche.
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MESH Headings
- Animals
- Female
- Glycoproteins/genetics
- Glycoproteins/metabolism
- HL-60 Cells
- Hematopoiesis
- Hematopoietic Stem Cells/metabolism
- Hematopoietic Stem Cells/pathology
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Male
- Mesenchymal Stem Cells/metabolism
- Mesenchymal Stem Cells/pathology
- Mice
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- U937 Cells
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Affiliation(s)
- Alexander Waclawiczek
- Haematopoietic Stem Cell Laboratory, Francis Crick Institute, London, United Kingdom
| | - Ashley Hamilton
- Haematopoietic Stem Cell Laboratory, Francis Crick Institute, London, United Kingdom
| | - Kevin Rouault-Pierre
- Haematopoietic Stem Cell Laboratory, Francis Crick Institute, London, United Kingdom
| | - Ander Abarrategi
- Haematopoietic Stem Cell Laboratory, Francis Crick Institute, London, United Kingdom
| | | | - Farideh Miraki-Moud
- Haemato-Oncology Unit, Royal Marsden Hospital, Institute of Cancer Research, London, United Kingdom
| | - Nourdine Bah
- Bioinformatic Core Facility, Francis Crick Institute, London, United Kingdom
| | - John Gribben
- Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Jude Fitzgibbon
- Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - David Taussig
- Haemato-Oncology Unit, Royal Marsden Hospital, Institute of Cancer Research, London, United Kingdom
| | - Dominique Bonnet
- Haematopoietic Stem Cell Laboratory, Francis Crick Institute, London, United Kingdom
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44
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Bento LC, Bacal NS, Rocha FA, Severino P, Marti LC. Bone Marrow Monocytes and Derived Dendritic Cells from Myelodysplastic Patients Have Functional Abnormalities Associated with Defective Response to Bacterial Infection. THE JOURNAL OF IMMUNOLOGY 2020; 204:2098-2109. [PMID: 32179638 DOI: 10.4049/jimmunol.1900328] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 02/06/2020] [Indexed: 01/14/2023]
Abstract
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell diseases characterized by dysplasia of one or more hematologic lineages and a high risk of developing into acute myeloid leukemia. MDS patients have recurrent bacterial infections and abnormal expression of CD56 by monocytes. We investigated MDS patients' bone marrow CD56+/CD56- monocytes and their in vitro-derived dendritic cell populations in comparison with cells obtained from disease-free subjects. We found that monocytes from MDS patients, irrespective of CD56 expression, have reduced phagocytosis activity and low expression of genes involved in triggering immune responses, regulation of immune and inflammatory response signaling pathways, and in the response to LPS. Dendritic cells derived in vitro from MDS monocytes failed to develop dendritic projections and had reduced expression of HLA-DR and CD86, suggesting that Ag processing and T cell activation capabilities are impaired. In conclusion, we identified, in both CD56+ and CD56- monocytes from MDS patients, several abnormalities that may be related to the increased susceptibility to infections observed in these patients.
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Affiliation(s)
- Laiz C Bento
- Clinical Pathology Laboratory, Hospital Israelita Albert Einstein, São Paulo 05652 000, Brazil; and
| | - Nydia S Bacal
- Clinical Pathology Laboratory, Hospital Israelita Albert Einstein, São Paulo 05652 000, Brazil; and
| | - Fernanda A Rocha
- Experimental Research Laboratory, Hospital Israelita Albert Einstein, São Paulo 05652 000, Brazil
| | - Patricia Severino
- Experimental Research Laboratory, Hospital Israelita Albert Einstein, São Paulo 05652 000, Brazil
| | - Luciana C Marti
- Experimental Research Laboratory, Hospital Israelita Albert Einstein, São Paulo 05652 000, Brazil
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45
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Hellmich C, Moore JA, Bowles KM, Rushworth SA. Bone Marrow Senescence and the Microenvironment of Hematological Malignancies. Front Oncol 2020; 10:230. [PMID: 32161723 PMCID: PMC7052485 DOI: 10.3389/fonc.2020.00230] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 02/11/2020] [Indexed: 12/11/2022] Open
Abstract
Senescence is the irreversible arrest of cell proliferation that has now been shown to play an important role in both health and disease. With increasing age senescent cells accumulate throughout the body, including the bone marrow and this has been associated with a number of age-related pathologies including malignancies. It has been shown that the senescence associated secretory phenotype (SASP) creates a pro-tumoural environment that supports proliferation and survival of malignant cells. Understanding the role of senescent cells in tumor development better may help us to identify new treatment targets to impair tumor survival and reduce treatment resistance. In this review, we will specifically discuss the role of senescence in the aging bone marrow (BM) microenvironment. Many BM disorders are age-related diseases and highly dependent on the BM microenvironment. Despite advances in drug development the prognosis particularly for older patients remains poor and new treatment approaches are needed to improve outcomes for patients. In this review, we will focus on the relationship of senescence and hematological malignancies, how senescence promotes cancer development and how malignant cells induce senescence.
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Affiliation(s)
- Charlotte Hellmich
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom.,Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, United Kingdom
| | - Jamie A Moore
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Kristian M Bowles
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom.,Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, United Kingdom
| | - Stuart A Rushworth
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom
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46
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Singh AK, Cancelas JA. Gap Junctions in the Bone Marrow Lympho-Hematopoietic Stem Cell Niche, Leukemia Progression, and Chemoresistance. Int J Mol Sci 2020; 21:E796. [PMID: 31991829 PMCID: PMC7038046 DOI: 10.3390/ijms21030796] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/19/2020] [Accepted: 01/23/2020] [Indexed: 12/15/2022] Open
Abstract
Abstract: The crosstalk between hematopoietic stem cells (HSC) and bone marrow (BM) microenvironment is critical for homeostasis and hematopoietic regeneration in response to blood formation emergencies after injury, and has been associated with leukemia transformation and progression. Intercellular signals by the BM stromal cells in the form of cell-bound or secreted factors, or by physical interaction, regulate HSC localization, maintenance, and differentiation within increasingly defined BM HSC niches. Gap junctions (GJ) are comprised of arrays of membrane embedded channels formed by connexin proteins, and control crucial signaling functions, including the transfer of ions, small metabolites, and organelles to adjacent cells which affect intracellular mechanisms of signaling and autophagy. This review will discuss the role of GJ in both normal and leukemic hematopoiesis, and highlight some of the most novel approaches that may improve the efficacy of cytotoxic drugs. Connexin GJ channels exert both cell-intrinsic and cell-extrinsic effects on HSC and BM stromal cells, involved in regenerative hematopoiesis after myelosuppression, and represent an alternative system of cell communication through a combination of electrical and metabolic coupling as well as organelle transfer in the HSC niche. GJ intercellular communication (GJIC) in the HSC niche improves cellular bioenergetics, and rejuvenates damaged recipient cells. Unfortunately, they can also support leukemia proliferation and survival by creating leukemic niches that provide GJIC dependent energy sources and facilitate chemoresistance and relapse. The emergence of new strategies to disrupt self-reinforcing malignant niches and intercellular organelle exchange in leukemic niches, while at the same time conserving normal hematopoietic GJIC function, could synergize the effect of chemotherapy drugs in eradicating minimal residual disease. An improved understanding of the molecular basis of connexin regulation in normal and leukemic hematopoiesis is warranted for the re-establishment of normal hematopoiesis after chemotherapy.
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Affiliation(s)
- Abhishek K. Singh
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA;
- Hoxworth Blood Center, University of Cincinnati Academic Health Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA
| | - Jose A. Cancelas
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA;
- Hoxworth Blood Center, University of Cincinnati Academic Health Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA
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Bone marrow mesenchymal stromal cells from acute myelogenous leukemia patients demonstrate adipogenic differentiation propensity with implications for leukemia cell support. Leukemia 2019; 34:391-403. [PMID: 31492897 PMCID: PMC7214245 DOI: 10.1038/s41375-019-0568-8] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 06/28/2019] [Accepted: 07/17/2019] [Indexed: 12/21/2022]
Abstract
Bone marrow mesenchymal stromal cells (MSCs) constitute one of the important components of the hematopoietic microenvironmental niche. In vivo studies have shown that depletion of marrow MSCs resulted in reduction of hematopoietic stem cell content, and there is in vitro evidence that marrow MSCs are able to support leukemia progenitor cell proliferation and survival and provide resistance to cytotoxic therapies. How MSCs from leukemia marrow differ from normal counterparts and how they are influenced by the presence of leukemia stem and progenitor cells are still incompletely understood. In this work, we compared normal donor (ND) and acute myelogenous leukemia (AML) derived MSCs and found that AML-MSCs had increased adipogenic potential with improved ability to support survival of leukemia progenitor cells. To identify underlying changes, RNA-Seq analysis was performed. Gene ontology and pathway analysis revealed adipogenesis to be among the set of altered biological pathways dysregulated in AML-MSCs as compared with ND-MSCs. Expression of both SOX9 and EGR2 was decreased in AML-MSCs as compared with ND-MSCs. Increasing expression of SOX9 decreased adipogenic potential of AML-MSCs and decreased their ability to support AML progenitor cells. These findings suggest that AML-MSCs possess adipogenic potential which may enhance support of leukemia progenitor cells.
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Targeting Leukemia Stem Cell-Niche Dynamics: A New Challenge in AML Treatment. JOURNAL OF ONCOLOGY 2019; 2019:8323592. [PMID: 31485227 PMCID: PMC6702816 DOI: 10.1155/2019/8323592] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Accepted: 07/18/2019] [Indexed: 01/02/2023]
Abstract
One of the most urgent needs in AML is to improve the disease cure rate as relapse still occurs in 60–80% of patients. Recent evidence suggests that dismal clinical outcomes may be improved by a better definition of the tight interaction between the AML cell population and the bone marrow (BM) microenvironment (“the niche”); the latter has been progressively highlighted to have an active role in the disease process. It has now been well established that the leukemic population may misinterpret niche-derived signals and remodel the niche, providing a shelter to AML cells and protecting them from the cytotoxic effects of chemoradiotherapy. Novel imaging technological advances and preclinical disease models have revealed that, due to the finite number of BM niches, leukemic stem cells (LSCs) and normal hematopoietic stem cells (HSCs) compete for the same functional areas. Thus, the removal of LSCs from the BM niche and the promotion of normal HSC engraftment should be the primary goals in antileukemic research. In addition, it is now becoming increasingly clear that AML-niche dynamics are disease stage specific. In AML, the niche has been linked to disease pathogenesis in the preleukemic stage, the niche becomes permissive once leukemic cells are established, and the niche is transformed into a self-reinforcing structure at a later disease stage. These concepts have been fostered by the demonstration that, in unrelated AML types, endosteal vessel loss occurs as a primary AML-induced niche alteration, and additional AML-induced alterations of the niche and normal hematopoiesis evolve focally and in parallel. Obviously, this endosteal vessel loss plays a fundamental role in AML pathogenesis by causing excessive vascular permeability, hypoxia, altered perfusion, and reduced drug delivery. Each of these alterations may be effectively targeted by various therapeutic procedures, but preservation of endosteal vessel integrity might be the best option for any future antileukemic treatment.
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Abdelhamed S, Butler JT, Doron B, Halse A, Nemecek E, Wilmarth PA, Marks DL, Chang BH, Horton T, Kurre P. Extracellular vesicles impose quiescence on residual hematopoietic stem cells in the leukemic niche. EMBO Rep 2019; 20:e47546. [PMID: 31267709 PMCID: PMC6607014 DOI: 10.15252/embr.201847546] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 05/03/2019] [Accepted: 05/13/2019] [Indexed: 01/19/2023] Open
Abstract
Progressive remodeling of the bone marrow microenvironment is recognized as an integral aspect of leukemogenesis. Expanding acute myeloid leukemia (AML) clones not only alter stroma composition, but also actively constrain hematopoiesis, representing a significant source of patient morbidity and mortality. Recent studies revealed the surprising resistance of long-term hematopoietic stem cells (LT-HSC) to elimination from the leukemic niche. Here, we examine the fate and function of residual LT-HSC in the BM of murine xenografts with emphasis on the role of AML-derived extracellular vesicles (EV). AML-EV rapidly enter HSC, and their trafficking elicits protein synthesis suppression and LT-HSC quiescence. Mechanistically, AML-EV transfer a panel of miRNA, including miR-1246, that target the mTOR subunit Raptor, causing ribosomal protein S6 hypo-phosphorylation, which in turn impairs protein synthesis in LT-HSC. While HSC functionally recover from quiescence upon transplantation to an AML-naive environment, they maintain relative gains in repopulation capacity. These phenotypic changes are accompanied by DNA double-strand breaks and evidence of a sustained DNA-damage response. In sum, AML-EV contribute to niche-dependent, reversible quiescence and elicit persisting DNA damage in LT-HSC.
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MESH Headings
- Animals
- Cell Line, Tumor
- Cells, Cultured
- DNA Breaks, Double-Stranded
- Extracellular Vesicles/metabolism
- Female
- Hematopoietic Stem Cells/metabolism
- Hematopoietic Stem Cells/pathology
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Male
- Mice
- Mice, Inbred C57BL
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Regulatory-Associated Protein of mTOR/genetics
- Regulatory-Associated Protein of mTOR/metabolism
- Ribosomal Protein S6/genetics
- Stem Cell Niche
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Affiliation(s)
- Sherif Abdelhamed
- Department of PediatricsPapé Family Pediatric Research InstituteOregon Health & Science UniversityPortlandORUSA
- Knight Cancer InstituteOregon Health & Science UniversityPortlandORUSA
| | - John T Butler
- Department of PediatricsPapé Family Pediatric Research InstituteOregon Health & Science UniversityPortlandORUSA
- Department of Biomedical EngineeringOregon Health & Science UniversityPortlandORUSA
| | - Ben Doron
- Department of PediatricsPapé Family Pediatric Research InstituteOregon Health & Science UniversityPortlandORUSA
| | - Amber Halse
- Department of PediatricsPapé Family Pediatric Research InstituteOregon Health & Science UniversityPortlandORUSA
| | - Eneida Nemecek
- Department of PediatricsPapé Family Pediatric Research InstituteOregon Health & Science UniversityPortlandORUSA
- Knight Cancer InstituteOregon Health & Science UniversityPortlandORUSA
| | - Phillip A Wilmarth
- Department of Biochemistry and Molecular BiologyOregon Health & Science UniversityPortlandORUSA
- Proteomics Shared ResourcesOregon Health & Science UniversityPortlandORUSA
| | - Daniel L Marks
- Department of PediatricsPapé Family Pediatric Research InstituteOregon Health & Science UniversityPortlandORUSA
- Knight Cancer InstituteOregon Health & Science UniversityPortlandORUSA
- Brenden‐Colson Center for Pancreatic CareOregon Health & Science UniversityPortlandORUSA
| | - Bill H Chang
- Department of PediatricsPapé Family Pediatric Research InstituteOregon Health & Science UniversityPortlandORUSA
- Knight Cancer InstituteOregon Health & Science UniversityPortlandORUSA
| | - Terzah Horton
- Texas Children's Cancer and Hematology CentersBaylor College of MedicineHoustonTXUSA
| | - Peter Kurre
- Children's Hospital of PhiladelphiaComprehensive Bone Marrow Failure CenterPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
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Rebound Thrombocytosis after Induction Chemotherapy is a Strong Biomarker for Favorable Outcome in AML Patients. Hemasphere 2019; 3:e180. [PMID: 31723819 PMCID: PMC6746035 DOI: 10.1097/hs9.0000000000000180] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Accepted: 01/20/2019] [Indexed: 11/29/2022] Open
Abstract
Whereas the molecular events underlying acute myeloid leukemia (AML) are increasingly identified, dynamics of hematologic recovery following induction chemotherapy remain mysterious. Platelet recovery may vary between incomplete and excess recovery among patients achieving remission. We analyzed platelet recovery after the first induction cycle in 291 consecutive AML patients. We defined excess platelet rebound (EPR) as platelet increase above 500 G/L. We observed EPR in 120 (41.2%) patients. EPR+ patients had lower platelets at diagnosis, higher marrow infiltration, more frequently NPM1 mutations, and were associated with ELN favorable risk. Absence of EPR correlated with complex karyotypes, ELN intermediate-I and adverse risk, and therapy-related AML. Overall survival was better in EPR+ patients than EPR- (median 125 vs 41 months; p = 0.04), as was disease-free survival. By multivariate analysis, EPR+ was an independent parameter associated with favorable survival. Plasma thrombopoietin (TPO) levels at diagnosis indicated EPR+ (p < 0.0001), while GATA-1, GATA-2, and MPL mRNA expression did not differ between EPR+ and EPR- patients. Finally, transcription factors blocking early megakaryopoiesis were upregulated in EPR- patients, while NFE2 involved in late megakaryocyte differentiation was increased in EPR+ patients. Our work identifies mechanisms involved in platelet recovery after induction chemotherapy.
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