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.
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Acknowledgements
This work was supported in part by the China National High Tech Program for Biotechnology (863:2006AA02A405), Chinese National Key Basic Research Project (973: 2010CB529203), the National Natural Science Foundation of China (30772744, 30821063, 81000213) and the Shanghai Municipal Commission for Science and Technology (07DZ05908,08DZ2200100). We thank Jiangsu Institute of Hematology of the First Affiliated Hospital of Soochow University, Department of Hematology of the First Affiliated Hospital of Zhejiang University, Department of Hematology of the Tongji Hospital of Tongji University and Department of Hematology of Luwan division of Ruijin Hospital for providing AML-M5 samples. We are grateful to W.-L. Zhao, F. Yang, Y.-Y. Wang and X. Fan for assistance in clinical analysis of the AML-M5 samples, and to B. Chen and S.-M. Xiong for carrying out the hematological morphological analysis.
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S.-J.C. and Z.C. were the principal investigators who conceived the study. S.-J.C., Z.C. and X.-J.Y. coordinated and oversaw the study. X.-J.Y. and J.X. carried out most of the experiments. Z.-H.G. and G.L. were responsible for bioinformatics investigation. C.-M.P. and H.-D.S. carried out the exome sequencing and participated in the validation experiments. J.-Q.M. and L.T. participated in the preparation of biological samples. Y.S. helped gather detailed clinical information for the study and helped to carry out clinical analysis. Y.-M.Z. and J.-Y.S. participated in the PCR assay and Sequenom analysis. X.-W.Z. and W.-X.L. helped to carry out the biochemical experiments. K.-Q.L. carried out the structural analysis and guided the biochemical experiments. Z.C., S.-J.C. and X.-J.Y. wrote the manuscript.
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Yan, XJ., Xu, J., Gu, ZH. et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 43, 309–315 (2011). https://doi.org/10.1038/ng.788
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DOI: https://doi.org/10.1038/ng.788
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