Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development.
Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development.
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DOI：
10.1016/j.ccell.2016.05.008
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发表时间：
2016-07-11
期刊：
影响因子：
50.3
通讯作者：
Wang GG
中科院分区：
文献类型：
--
作者：
Lu R;Wang P;Parton T;Zhou Y;Chrysovergis K;Rockowitz S;Chen WY;Abdel-Wahab O;Wade PA;Zheng D;Wang GG
DNA甲基转移酶3A（DNMT 3A）在血液癌症中经常发生突变;然而，潜在的致癌机制仍然难以捉摸。在这里，我们报告DNMT 3A突变热点Arg 882（DNMT 3AR 882 H）与NRAS突变合作转化造血干/祖细胞并诱导急性白血病的发展。在机制上，DNMT 3AR 882 H直接结合到对白血病发生至关重要的干性基因（包括Meis 1、Mn 1和Hoxa基因簇）并增强其反式激活。DNMT 3AR 882 H诱导局灶性表观遗传改变，包括CpG低甲基化和同时获得活性组蛋白修饰，在顺式调节元件如增强子处促进基因转录。CRISPR/Cas9介导的携带DNMT 3AR 882 H诱导的DNA低甲基化的推定Meis 1增强子的消融损害Meis 1表达。重要的是，DNMT 3AR 882 H诱导的基因表达程序可以通过Dot 11抑制来抑制，为DNMT 3A突变的白血病提供了一种有吸引力的治疗策略。Lu等人确定Arg 882突变的DNMT 3A通过白血病相关基因的表观遗传激活促进急性髓性白血病（AML）发病机制。Dot 1 l的抑制逆转突变体DNMT 3A诱导的基因表达，表明一种潜在的治疗策略，为AML携带这种突变。
DNA methyltransferase 3A (DNMT3A) is frequently mutated in hematological cancers; however, the underlying oncogenic mechanism remains elusive. Here, we report that DNMT3A mutational hotspot at Arg882 (DNMT3AR882H) cooperates with NRAS mutation to transform hematopoietic stem/progenitor cells and induce acute leukemia development. Mechanistically, DNMT3AR882H directly binds to and potentiates transactivation of stemness genes critical for leukemogenicity including Meis1, Mn1 and Hoxa gene cluster. DNMT3AR882H induces focal epigenetic alterations, including CpG hypomethylation and concurrent gain of active histone modifications, at cis-regulatory elements such as enhancers to facilitate gene transcription. CRISPR/Cas9-mediated ablation of a putative Meis1 enhancer carrying DNMT3AR882H-induced DNA hypomethylation impairs Meis1 expression. Importantly, DNMT3AR882H-induced gene expression programs can be repressed through Dot1l inhibition, providing an attractive therapeutic strategy for DNMT3A-mutated leukemias. Lu et al. establish that Arg882-mutated DNMT3A contributes to acute myeloid leukemia (AML) pathogenesis through epigenetic activation of leukemia-related genes. Inhibition of Dot1l reverses mutant DNMT3A-induced gene expression, indicating a potential therapeutic strategy for AMLs harboring this mutation.