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

作者：Jie Xu, Yueying Wang, Yu‐Jun Dai, Wu Zhang, Weina Zhang, Shu-Min Xiong, Zhaohui Gu, Kankan Wang, Rong Zeng, Chen Zhu, Sai‐Juan Chen · 发表于：Proceedings of the National Academy of Sciences · 年份：2014 · DOI：10.1073/pnas.1400150111 · 被引用次数：103 · 研究领域：Acute Myeloid Leukemia Research、Myeloproliferative Neoplasms: Diagnosis and Treatment、Epigenetics and DNA Methylation

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.