Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene expression program and acute leukemia development

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 (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.

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Lu R, Wang P, Parton T, Zhou Y, Chrysovergis K, Rockowitz S, Chen WY, Abdel-Wahab O, Wade PA, Zheng D, Wang GG