Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development

Rui Lu, Ping Wang, Trevor Parton, Yang Zhou, Kaliopi Chrysovergis, Shira Rockowitz, Wei Yi Chen, Omar Abdel-Wahab, Paul A. Wade, Deyou Zheng, Gang Greg Wang

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

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 (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.

Original languageEnglish (US)
Pages (from-to)92-107
Number of pages16
JournalCancer Cell
Volume30
Issue number1
DOIs
StatePublished - Jul 11 2016

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Lu, R., Wang, P., Parton, T., Zhou, Y., Chrysovergis, K., Rockowitz, S., Chen, W. Y., Abdel-Wahab, O., Wade, P. A., Zheng, D., & Wang, G. G. (2016). Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development. Cancer Cell, 30(1), 92-107. https://doi.org/10.1016/j.ccell.2016.05.008