Contribution of mutant HSC clones to immature and mature cells in MDS and CMML, and variations with AZA 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..
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.
| Errataetall: |
CommentIn: Blood. 2023 Mar 16;141(11):1243-1245. - PMID 36929441 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:141 |
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| Enthalten in: |
Blood - 141(2023), 11 vom: 16. März, Seite 1316-1321 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schnegg-Kaufmann, Annatina S [VerfasserIn] |
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| Anmerkungen: |
Date Completed 21.03.2023 Date Revised 13.03.2024 published: Print CommentIn: Blood. 2023 Mar 16;141(11):1243-1245. - PMID 36929441 Citation Status MEDLINE |
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| doi: |
10.1182/blood.2022018602 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Contribution of mutant HSC clones to immature and mature cells in MDS and CMML, and variations with AZA therapy |
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| 500 | |a CommentIn: Blood. 2023 Mar 16;141(11):1243-1245. - PMID 36929441 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 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. | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Thoms, Julie A I |e verfasserin |4 aut | |
| 700 | 1 | |a Bhuyan, Golam Sarower |e verfasserin |4 aut | |
| 700 | 1 | |a Hampton, Henry R |e verfasserin |4 aut | |
| 700 | 1 | |a Vaughan, Lachlin |e verfasserin |4 aut | |
| 700 | 1 | |a Rutherford, Kayleigh |e verfasserin |4 aut | |
| 700 | 1 | |a Kakadia, Purvi M |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Hui Mei |e verfasserin |4 aut | |
| 700 | 1 | |a Johansson, Emma M V |e verfasserin |4 aut | |
| 700 | 1 | |a Failes, Timothy W |e verfasserin |4 aut | |
| 700 | 1 | |a Arndt, Greg M |e verfasserin |4 aut | |
| 700 | 1 | |a Koval, Jason |e verfasserin |4 aut | |
| 700 | 1 | |a Lindeman, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Warburton, Pauline |e verfasserin |4 aut | |
| 700 | 1 | |a Rodriguez-Meira, Alba |e verfasserin |4 aut | |
| 700 | 1 | |a Mead, Adam J |e verfasserin |4 aut | |
| 700 | 1 | |a Unnikrishnan, Ashwin |e verfasserin |4 aut | |
| 700 | 1 | |a Davidson, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Polizzotto, Mark N |e verfasserin |4 aut | |
| 700 | 1 | |a Hertzberg, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Papaemmanuil, Elli |e verfasserin |4 aut | |
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| 700 | 1 | |a Faridani, Omid R |e verfasserin |4 aut | |
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| 700 | 1 | |a Zanini, Fabio |e verfasserin |4 aut | |
| 700 | 1 | |a Pimanda, John E |e verfasserin |4 aut | |
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