@article{6888b9d1c6c6441f813c77bf6a563793,
title = "Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy",
abstract = "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.",
keywords = "HSC exhaustion, Kmt2c, MLL3, hematopoietic stem cell, interleukin-1, self-renewal, therapy-related leukemia",
author = "Ran Chen and Theresa Okeyo-Owuor and Patel, {Riddhi M.} and Casey, {Emily B.} and Cluster, {Andrew S.} and Wei Yang and Magee, {Jeffrey A.}",
note = "Funding Information: This work was supported by grants to J.A.M. from the NHLBI ( R01 HL152180 and R01 HL136504 ), Alex{\textquoteright}s Lemonade Stand Foundation ({\textquoteleft}A{\textquoteright} Award), Gabrielle's Angel Foundation , The V Foundation , the American Society of Hematology , Hyundai Hope on Wheels , and the Children{\textquoteright}s Discovery Institute of Washington University and St. Louis Children{\textquoteright}s Hospital . We thank the Genome Engineering and iPSC Center and the Department of Pathology Micro-injection Core at Washington University for assistance in generating mouse lines. We thank Todd Druley for helpful discussions. Funding Information: This work was supported by grants to J.A.M. from the NHLBI (R01 HL152180 and R01 HL136504), Alex's Lemonade Stand Foundation (?A? Award), Gabrielle's Angel Foundation, The V Foundation, the American Society of Hematology, Hyundai Hope on Wheels, and the Children's Discovery Institute of Washington University and St. Louis Children's Hospital. We thank the Genome Engineering and iPSC Center and the Department of Pathology Micro-injection Core at Washington University for assistance in generating mouse lines. We thank Todd Druley for helpful discussions. J.A.M. designed and oversaw all experiments, conducted experiments, interpreted data, wrote the manuscript, and secured funding. R.C. conducted experiments, interpreted data, and wrote the manuscript. T.O.-O. R.M.P. E.B.C. and A.S.C. performed experiments and interpreted data. W.Y. performed all bioinformatic analyses. All authors reviewed and edited the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = feb,
day = "16",
doi = "10.1016/j.celrep.2021.108751",
language = "English",
volume = "34",
journal = "Cell Reports",
issn = "2211-1247",
number = "7",
}