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Cancer Cell. 2014 Apr 14;25(4):442-54. doi: 10.1016/j.ccr.2014.02.010. Epub 2014 Mar 20.

The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers.

Author information

1
Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
2
Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA.
3
The Genome Institute, Washington University, St. Louis, MO 63110, USA.
4
Division of Metabolism, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
5
Division of Metabolism, Department of Medicine, Washington University, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA.
6
The Genome Institute, Washington University, St. Louis, MO 63110, USA; Department of Genetics, Washington University, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA.
7
Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA; The Genome Institute, Washington University, St. Louis, MO 63110, USA; Department of Genetics, Washington University, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA. Electronic address: timley@wustl.edu.

Abstract

Somatic mutations in DNMT3A, which encodes a de novo DNA methyltransferase, are found in ∼30% of normal karyotype acute myeloid leukemia (AML) cases. Most mutations are heterozygous and alter R882 within the catalytic domain (most commonly R882H), suggesting the possibility of dominant-negative consequences. The methyltransferase activity of R882H DNMT3A is reduced by ∼80% compared with the WT enzyme. In vitro mixing of WT and R882H DNMT3A does not affect the WT activity, but coexpression of the two proteins in cells profoundly inhibits the WT enzyme by disrupting its ability to homotetramerize. AML cells with the R882H mutation have severely reduced de novo methyltransferase activity and focal hypomethylation at specific CpGs throughout AML cell genomes.

PMID:
24656771
PMCID:
PMC4018976
DOI:
10.1016/j.ccr.2014.02.010
[Indexed for MEDLINE]
Free PMC Article

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