title: Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development.
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 (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.
authors.affiliation: 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Parton
authors.affiliation: Department of Pathology and Laboratory Medicine, McAllister Heart Institute, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Kaliopi
authors.initials: K
authors.lastname: Chrysovergis
authors.affiliation: Departments of Genetics and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Shira
authors.initials: S
authors.lastname: Rockowitz
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wade
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Genetics and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: deyou.zheng@einstein.yu.edu.
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.affiliation: 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; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: greg_wang@med.unc.edu.
authors.forename: Gang Greg
authors.initials: GG
authors.lastname: Wang
mesh_terms: D000818:Animals; D001120:Arginine / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D011905:Genes, ras; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D051379:Mice; D009154:Mutation; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009374:Neoplasms, Experimental; D011401:Promoter Regions, Genetic; D013234:Stem Cells / Q000166:cytology / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D001120:Arginine; D008780:Methyltransferases; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A