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DNMT3A Arg882 mutation drives chronic myelomonocytic leukemia through disturbing gene expression/DNA methylation in hematopoietic cells.

ABSTRACT: The gene encoding DNA methyltransferase 3A (DNMT3A) is mutated in ?20% of acute myeloid leukemia cases, with Arg882 (R882) as the hotspot. Here, we addressed the transformation ability of the DNMT3A-Arg882His (R882H) mutant by using a retroviral transduction and bone marrow transplantation (BMT) approach and found that the mutant gene can induce aberrant proliferation of hematopoietic stem/progenitor cells. At 12 mo post-BMT, all mice developed chronic myelomonocytic leukemia with thrombocytosis. RNA microarray analysis revealed abnormal expressions of some hematopoiesis-related genes, and the DNA methylation assay identified corresponding changes in methylation patterns in gene body regions. Moreover, DNMT3A-R882H increased the CDK1 protein level and enhanced cell-cycle activity, thereby contributing to leukemogenesis.

SUBMITTER: Xu J 

PROVIDER: S-EPMC3932885 | biostudies-other | 2014 Feb

REPOSITORIES: biostudies-other

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DNMT3A Arg882 mutation drives chronic myelomonocytic leukemia through disturbing gene expression/DNA methylation in hematopoietic cells.

Xu Jie J   Wang Yue-Ying YY   Dai Yu-Jun YJ   Zhang Wu W   Zhang Wei-Na WN   Xiong Shu-Min SM   Gu Zhao-Hui ZH   Wang Kan-Kan KK   Zeng Rong R   Chen Zhu Z   Chen Sai-Juan SJ  

Proceedings of the National Academy of Sciences of the United States of America 20140204 7

The gene encoding DNA methyltransferase 3A (DNMT3A) is mutated in ∼20% of acute myeloid leukemia cases, with Arg882 (R882) as the hotspot. Here, we addressed the transformation ability of the DNMT3A-Arg882His (R882H) mutant by using a retroviral transduction and bone marrow transplantation (BMT) approach and found that the mutant gene can induce aberrant proliferation of hematopoietic stem/progenitor cells. At 12 mo post-BMT, all mice developed chronic myelomonocytic leukemia with thrombocytosis  ...[more]

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