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

Authors :
Annatina S. Schnegg-Kaufmann
Julie A. I. Thoms
Golam Sarower Bhuyan
Henry R. Hampton
Lachlin Vaughan
Kayleigh Rutherford
Purvi M. Kakadia
Hui Mei Lee
Emma M. V. Johansson
Timothy W. Failes
Greg M. Arndt
Jason Koval
Robert Lindeman
Pauline Warburton
Alba Rodriguez-Meira
Adam J. Mead
Ashwin Unnikrishnan
Sarah Davidson
Mark N. Polizzotto
Mark Hertzberg
Elli Papaemmanuil
Stefan K. Bohlander
Omid R. Faridani
Christopher J. Jolly
Fabio Zanini
John E. Pimanda
Source :
Blood.
Publication Year :
2022

Abstract

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.

Details

ISSN :
15280020
Database :
OpenAIRE
Journal :
Blood
Accession number :
edsair.doi.dedup.....d50a9f170969169a21dc1d1c24b8d9e9