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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 na\u00efve 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\u00a0vivo. Increased contributions from productive mutant progenitors appear to underlie improved hematopoiesis in MDS following HMA therapy.<\/jats:p>","DOI":"10.1182\/blood.2022018602","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T21:07:17Z","timestamp":1670620037000},"page":"1316-1321","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":20,"title":["Contribution of mutant HSC clones to immature and mature cells in MDS and CMML, and variations with AZA therapy"],"prefix":"10.1182","volume":"141","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7716-3340","authenticated-orcid":false,"given":"Annatina S.","family":"Schnegg-Kaufmann","sequence":"first","affiliation":[{"name":"1School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia"},{"name":"2Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland"},{"name":"3Department for Biomedical Research, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4876-7230","authenticated-orcid":false,"given":"Julie A. 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