TY - JOUR
T1 - Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development
AU - Lu, Rui
AU - Wang, Ping
AU - Parton, Trevor
AU - Zhou, Yang
AU - Chrysovergis, Kaliopi
AU - Rockowitz, Shira
AU - Chen, Wei Yi
AU - Abdel-Wahab, Omar
AU - Wade, Paul A.
AU - Zheng, Deyou
AU - Wang, Gang Greg
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/7/11
Y1 - 2016/7/11
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ccell.2016.05.008
DO - 10.1016/j.ccell.2016.05.008
M3 - Article
C2 - 27344947
AN - SCOPUS:84979781455
SN - 1535-6108
VL - 30
SP - 92
EP - 107
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -