DNMT3A Arg882 mutation drives chronic myelomonocytic leukemia through disturbing gene expression/DNA methylation in hematopoietic cells.
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.
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Jie
J
Xu
Yue-Ying
YY
Wang
Yu-Jun
YJ
Dai
Wu
W
Zhang
Wei-Na
WN
Zhang
Shu-Min
SM
Xiong
Zhao-Hui
ZH
Gu
Kan-Kan
KK
Wang
Rong
R
Zeng
Zhu
Z
Chen
Sai-Juan
SJ
Chen
D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D016130:Immunophenotyping; D047468:Immunoprecipitation; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics*; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D046228:Microarray Analysis; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics
C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
epigenetic abnormality; genomic variation; leukemogenic effect