Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy.
Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy.
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Kmt2c突变增强HSC自我更新能力，并在化疗后传达选择性优势。
DOI：
10.1016/j.celrep.2021.108751
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发表时间：
2021-02-16
期刊：
影响因子：
8.8
通讯作者：
Magee JA
中科院分区：
文献类型：
--
作者：
Chen R;Okeyo-Owuor T;Patel RM;Casey EB;Cluster AS;Yang W;Magee JA
骨髓肿瘤抑制因子KMT 2C在骨髓增生异常综合征（MDS）和急性髓性白血病（AML）中复发性缺失，特别是治疗相关的MDS/AML（t-MDS/t-AML），作为较大的7号染色体缺失的一部分。在这里，我们表明，KMT 2C缺失传达了选择性的优势，造血干细胞（HSC）化疗治疗后，可能沉淀t-MDS/t-AML。Kmt 2c缺失显著增强小鼠HSC自我更新能力而不改变增殖速率。单倍体Kmt 2c缺失仅在HSC被强增殖刺激（如化疗）驱动进入周期时才具有选择性优势。周期性Kmt 2c缺陷的HSC不能适当地分化，特别是响应于白细胞介素-1。Kmt 2c缺失减轻了组蛋白甲基化/乙酰化的变化，这些变化随着化疗后HSC的循环而增加，并且它们损害了HSC分化过程中增强子的募集。这些发现有助于解释为什么Kmt 2c缺失在t-MDS/t-AML中比在新生AML或克隆造血中更常见：它们选择性地保护循环HSC免于分化，而不诱导HSC本身增殖。Chen等人使用功能丧失小鼠来研究Kmt 2c/MLL 3在造血干细胞（HSC）自我更新中的作用。他们表明，当造血干细胞被化疗驱动进入周期时，特别是与白细胞介素-1暴露结合时，单倍体Kmt 2c缺失会阻碍分化。这传达了一个选择性的优势，可能会促进治疗相关的白血病。
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. Chen et al. use loss-of-function mice to study the role Kmt2c/MLL3 in hematopoietic stem cell (HSC) self-renewal. They show that haploid Kmt2c deletions impede differentiation when HSCs are driven into cycle by chemotherapy, especially in conjunction with interleukin-1 exposure. This conveys a selective advantage that may promote therapy-related leukemias.
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影响因子：
64.5
作者：
Bernitz, Jeffrey M.;Kim, Huen Suk;MacArthur, Ben;Sieburg, Hans;Moore, Kateri
通讯作者：
Moore, Kateri
影响因子：
8.8
作者：
Jozwik KM;Chernukhin I;Serandour AA;Nagarajan S;Carroll JS
通讯作者：
Carroll JS
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
3.7
作者：
Arcipowski KM;Bulic M;Gurbuxani S;Licht JD
通讯作者：
Licht JD
影响因子：
46.9
作者：
Foudi, Adlen;Hochedlinger, Konrad;Van Buren, Denille;Schindler, Jeffrey W.;Jaenisch, Rudolf;Carey, Vincent;Hock, Hanno
通讯作者：
Hock, Hanno