title: Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia.
abstract: Abnormal epigenetic regulation has been implicated in oncogenesis. We report here the identification of somatic mutations by exome sequencing in acute monocytic leukemia, the M5 subtype of acute myeloid leukemia (AML-M5). We discovered mutations in DNMT3A (encoding DNA methyltransferase 3A) in 23 of 112 (20.5%) cases. The DNMT3A mutants showed reduced enzymatic activity or aberrant affinity to histone H3 in vitro. Notably, there were alterations of DNA methylation patterns and/or gene expression profiles (such as HOXB genes) in samples with DNMT3A mutations as compared with those without such changes. Leukemias with DNMT3A mutations constituted a group of poor prognosis with elderly disease onset and of promonocytic as well as monocytic predominance among AML-M5 individuals. Screening other leukemia subtypes showed Arg882 alterations in 13.6% of acute myelomonocytic leukemia (AML-M4) cases. Our work suggests a contribution of aberrant DNA methyltransferase activity to the pathogenesis of acute monocytic leukemia and provides a useful new biomarker for relevant cases.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Yan
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Gu
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Pan
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Shi
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Zhu
authors.forename: Lin
authors.initials: L
authors.lastname: Tang
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Zhang
authors.forename: Wen-Xue
authors.initials: WX
authors.lastname: Liang
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: Mi
authors.forename: Huai-Dong
authors.initials: HD
authors.lastname: Song
authors.forename: Ke-Qin
authors.initials: KQ
authors.lastname: Li
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D017124:Conserved Sequence; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons; D005260:Female; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D053208:Kaplan-Meier Estimate; D007948:Leukemia, Monocytic, Acute / Q000201:enzymology* / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D020125:Mutation, Missense; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D011379:Prognosis; D017386:Sequence Homology, Amino Acid
chemical_list: D014408:Biomarkers, Tumor; D018076:DNA, Complementary; C000717967:DNMT3A protein, human; C497422:KMT2A protein, human; D050505:Mutant Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D011495:Histone-Lysine N-Methyltransferase