Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia.
paper
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- Authors
- Yan, Xiao-Jing; Xu, Jie; Gu, Zhao-Hui; Pan, Chun-Ming; Lu, Gang; Shen, Yang; Shi, Jing-Yi; Zhu, Yong-Mei; Tang, Lin; Zhang, Xiao-Wei; Liang, Wen-Xue; Mi, Jian-Qing; Song, Huai-Dong; Li, Ke-Qin; Chen, Zhu; Chen, Sai-Juan
- Year
- 2011
- Journal
- Nature genetics
- PMID
- 21399634
- DOI
- 10.1038/ng.788
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.
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