Lu Rui, Wang Ping, Parton Trevor, Zhou Yang, Chrysovergis Kaliopi, Rockowitz Shira, Chen Wei-Yi, Abdel-Wahab Omar, Wade Paul A, Zheng Deyou, Wang Gang Greg
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Cancer Cell. 2016 Jul 11;30(1):92-107. doi: 10.1016/j.ccell.2016.05.008. Epub 2016 Jun 23.
DNA methyltransferase 3A (DNMT3A) is frequently mutated in hematological cancers; however, the underlying oncogenic mechanism remains elusive. Here, we report that the DNMT3A mutational hotspot at Arg882 (DNMT3A(R882H)) cooperates with NRAS mutation to transform hematopoietic stem/progenitor cells and induce acute leukemia development. Mechanistically, DNMT3A(R882H) directly binds to and potentiates transactivation of stemness genes critical for leukemogenicity including Meis1, Mn1, and Hoxa gene cluster. DNMT3A(R882H) 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 DNMT3A(R882H)-induced DNA hypomethylation impairs Meis1 expression. Importantly, DNMT3A(R882H)-induced gene-expression programs can be repressed through Dot1l inhibition, providing an attractive therapeutic strategy for DNMT3A-mutated leukemias.
DNA甲基转移酶3A（DNMT3A）在血液系统癌症中经常发生突变；然而，其潜在的致癌机制仍不清楚。在此，我们报告，位于精氨酸882位点的DNMT3A突变热点（DNMT3A(R882H)）与NRAS突变协同作用，可转化造血干/祖细胞并诱导急性白血病的发生。从机制上讲，DNMT3A(R882H)直接结合并增强对白血病发生至关重要的干性基因的反式激活，这些基因包括Meis1、Mn1和Hoxa基因簇。DNMT3A(R882H)在诸如增强子等顺式调控元件处诱导局部表观遗传改变，包括CpG低甲基化和活性组蛋白修饰的同时增加，以促进基因转录。CRISPR/Cas9介导的对携带DNMT3A(R882H)诱导的DNA低甲基化的假定Meis1增强子的切除会损害Meis1的表达。重要的是，DNMT3A(R882H)诱导的基因表达程序可通过抑制Dot1l来抑制，这为DNMT3A突变的白血病提供了一种有吸引力的治疗策略。
