Contribution of mutant HSC clones to immature and mature cells in MDS and CMML, and variations with AZA therapy.

Autor:	Schnegg-Kaufmann AS; School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.; Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.; Department for Biomedical Research, University of Bern, Bern, Switzerland., Thoms JAI; School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia., Bhuyan GS; School of Clinical Medicine, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia., Hampton HR; School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia., Vaughan L; School of Clinical Medicine, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.; Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, NSW, Australia.; Haematology Department, Westmead Hospital, Sydney, NSW, Australia., Rutherford K; Department of Epidemiology and Biostatistics, Computational Oncology Service, Center for Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY., Kakadia PM; Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand., Lee HM; Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand., Johansson EMV; Flow Cytometry Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW, Australia., Failes TW; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.; Australian Cancer Research Foundation (ACRF) Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia., Arndt GM; School of Clinical Medicine, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.; Australian Cancer Research Foundation (ACRF) Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia., Koval J; Ramaciotti Centre for Genomics, UNSW Sydney, Sydney, NSW, Australia., Lindeman R; Department of Clinical Haematology, Prince of Wales Hospital, Sydney, NSW, Australia., Warburton P; Department of Haematology, Wollongong Hospital, Wollongong, NSW, Australia., Rodriguez-Meira A; Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Mead AJ; Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Unnikrishnan A; School of Clinical Medicine, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia., Davidson S; ANU Clinical Hub for Interventional Research (CHOIR), John Curtin School of Medical Research, Canberra, Australia., Polizzotto MN; ANU Clinical Hub for Interventional Research (CHOIR), John Curtin School of Medical Research, Canberra, Australia., Hertzberg M; Department of Clinical Haematology, Prince of Wales Hospital, Sydney, NSW, Australia., Papaemmanuil E; Department of Epidemiology and Biostatistics, Computational Oncology Service, Center for Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY., Bohlander SK; Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand., Faridani OR; School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.; Garvan-Weizmann Centre for Cellular Genomics, Sydney, NSW, Australia.; Cellular Genomics Futures Institute, UNSW Sydney, Sydney, NSW, Australia., Jolly CJ; School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia., Zanini F; School of Clinical Medicine, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.; Garvan-Weizmann Centre for Cellular Genomics, Sydney, NSW, Australia.; Cellular Genomics Futures Institute, UNSW Sydney, Sydney, NSW, Australia., Pimanda JE; School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.; School of Clinical Medicine, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.; Department of Clinical Haematology, Prince of Wales Hospital, Sydney, NSW, Australia.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 Mar 16; Vol. 141 (11), pp. 1316-1321.
DOI:	10.1182/blood.2022018602
Abstrakt:	Myelodysplastic neoplasms (MDSs) and chronic myelomonocytic leukemia (CMML) are clonal disorders driven by progressively acquired somatic mutations in hematopoietic stem cells (HSCs). Hypomethylating agents (HMAs) can modify the clinical course of MDS and CMML. Clinical improvement does not require eradication of mutated cells and may be related to improved differentiation capacity of mutated HSCs. However, in patients with established disease it is unclear whether (1) HSCs with multiple mutations progress through differentiation with comparable frequency to their less mutated counterparts or (2) improvements in peripheral blood counts following HMA therapy are driven by residual wild-type HSCs or by clones with particular combinations of mutations. To address these questions, the somatic mutations of individual stem cells, progenitors (common myeloid progenitors, granulocyte monocyte progenitors, and megakaryocyte erythroid progenitors), and matched circulating hematopoietic cells (monocytes, neutrophils, and naïve B cells) in MDS and CMML were characterized via high-throughput single-cell genotyping, followed by bulk analysis in immature and mature cells before and after AZA treatment. The mutational burden was similar throughout differentiation, with even the most mutated stem and progenitor clones maintaining their capacity to differentiate to mature cell types in vivo. Increased contributions from productive mutant progenitors appear to underlie improved hematopoiesis in MDS following HMA therapy. (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu