期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 7, 页码 2620-2625出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1400150111
关键词
genomic variation; epigenetic abnormality; leukemogenic effect
资金
- Chinese National Key Basic Research Project 973 [2010CB529200, 2013CB966800]
- Ministry of Health Grant [201202003]
- Mega-projects of Scientific Research [2013ZX09303302]
- State Key Laboratories Project of Excellence Grant [81123005]
- National Natural Science Foundation of China [81222004]
- Shanghai Municipal Commission [12QH1401500]
- Ministry of Education of China [20120073110074]
- Innovation Foundation for Doctoral Students of Shanghai Jiao Tong University School of Medicine [BXJ201208]
- Samuel Waxman Cancer Research Foundation Co-Principal Investigator Program
The gene encoding DNA methyltransferase 3A (DNMT3A) is mutated in similar to 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.
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