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.

• Authors: Jie Xu, Yue-Ying Wang, Yu-Jun Dai, Wu Zhang, Wei-Na Zhang, Shu-Min Xiong, Zhao-Hui Gu, Kan-Kan Wang, Rong Zeng, Zhu Chen, Sai-Juan Chen
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 7 Pg. 2620-5 (Feb 18 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24497509 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNMT3A protein, human
• Dnmt3a protein, mouse
• DNA (Cytosine-5-)-Methyltransferases
• DNA Methyltransferase 3A

Topics

• Animals
• Blotting, Western
• Cell Cycle (genetics, physiology)
• DNA (Cytosine-5-)-Methyltransferases (genetics)
• DNA Methylation (genetics)
• DNA Methyltransferase 3A
• Flow Cytometry
• Gene Expression Profiling
• Gene Expression Regulation (genetics)
• Hematopoietic Stem Cells (metabolism)
• Humans
• Immunoblotting
• Immunophenotyping
• Immunoprecipitation
• Leukemia, Myelomonocytic, Chronic (genetics)
• Mass Spectrometry
• Mice
• Mice, Inbred BALB C
• Microarray Analysis
• Mutagenesis, Site-Directed
• Mutation, Missense (genetics)