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Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy
The myeloid tumor suppressor KMT2C is recurrently deleted in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly therapy-related MDS/AML (t-MDS/t-AML), as part of larger chromosome 7 deletions. Here, we show that KMT2C deletions convey a selective advantage to hematopoietic...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951951/ https://www.ncbi.nlm.nih.gov/pubmed/33596429 http://dx.doi.org/10.1016/j.celrep.2021.108751 |
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author | Chen, Ran Okeyo-Owuor, Theresa Patel, Riddhi M. Casey, Emily B. Cluster, Andrew S. Yang, Wei Magee, Jeffrey A. |
author_facet | Chen, Ran Okeyo-Owuor, Theresa Patel, Riddhi M. Casey, Emily B. Cluster, Andrew S. Yang, Wei Magee, Jeffrey A. |
author_sort | Chen, Ran |
collection | PubMed |
description | The myeloid tumor suppressor KMT2C is recurrently deleted in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly therapy-related MDS/AML (t-MDS/t-AML), as part of larger chromosome 7 deletions. Here, we show that KMT2C deletions convey a selective advantage to hematopoietic stem cells (HSCs) after chemotherapy treatment that may precipitate t-MDS/t-AML. Kmt2c deletions markedly enhance murine HSC self-renewal capacity without altering proliferation rates. Haploid Kmt2c deletions convey a selective advantage only when HSCs are driven into cycle by a strong proliferative stimulus, such as chemotherapy. Cycling Kmt2c-deficient HSCs fail to differentiate appropriately, particularly in response to interleukin-1. Kmt2c deletions mitigate histone methylation/acetylation changes that accrue as HSCs cycle after chemotherapy, and they impair enhancer recruitment during HSC differentiation. These findings help explain why Kmt2c deletions are more common in t-MDS/t-AML than in de novo AML or clonal hematopoiesis: they selectively protect cycling HSCs from differentiation without inducing HSC proliferation themselves. |
format | Online Article Text |
id | pubmed-7951951 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-79519512021-03-11 Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy Chen, Ran Okeyo-Owuor, Theresa Patel, Riddhi M. Casey, Emily B. Cluster, Andrew S. Yang, Wei Magee, Jeffrey A. Cell Rep Article The myeloid tumor suppressor KMT2C is recurrently deleted in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly therapy-related MDS/AML (t-MDS/t-AML), as part of larger chromosome 7 deletions. Here, we show that KMT2C deletions convey a selective advantage to hematopoietic stem cells (HSCs) after chemotherapy treatment that may precipitate t-MDS/t-AML. Kmt2c deletions markedly enhance murine HSC self-renewal capacity without altering proliferation rates. Haploid Kmt2c deletions convey a selective advantage only when HSCs are driven into cycle by a strong proliferative stimulus, such as chemotherapy. Cycling Kmt2c-deficient HSCs fail to differentiate appropriately, particularly in response to interleukin-1. Kmt2c deletions mitigate histone methylation/acetylation changes that accrue as HSCs cycle after chemotherapy, and they impair enhancer recruitment during HSC differentiation. These findings help explain why Kmt2c deletions are more common in t-MDS/t-AML than in de novo AML or clonal hematopoiesis: they selectively protect cycling HSCs from differentiation without inducing HSC proliferation themselves. 2021-02-16 /pmc/articles/PMC7951951/ /pubmed/33596429 http://dx.doi.org/10.1016/j.celrep.2021.108751 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Chen, Ran Okeyo-Owuor, Theresa Patel, Riddhi M. Casey, Emily B. Cluster, Andrew S. Yang, Wei Magee, Jeffrey A. Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy |
title | Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy |
title_full | Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy |
title_fullStr | Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy |
title_full_unstemmed | Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy |
title_short | Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy |
title_sort | kmt2c mutations enhance hsc self-renewal capacity and convey a selective advantage after chemotherapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951951/ https://www.ncbi.nlm.nih.gov/pubmed/33596429 http://dx.doi.org/10.1016/j.celrep.2021.108751 |
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