A DNMT3A mutation common in AML exhibits dominant-negative effects in murine ES cells
Open accessAbstract
Somatic heterozygous mutations of the DNA methyltransferase gene DNMT3A occur frequently in acute myeloid leukemia and other hematological malignancies, with the majority (∼60%) of mutations affecting a single amino acid, Arg882 (R882), in the catalytic domain. Although the mutations impair DNMT3A catalytic activity in vitro, their effects on DNA methylation in cells have not been explored. Here, we show that exogenously expressed mouse Dnmt3a proteins harboring the corresponding R878 mutations largely fail to mediate DNA methylation in murine embryonic stem (ES) cells but are capable of interacting with wild-type Dnmt3a and Dnmt3b. Coexpression of the Dnmt3a R878H (histidine) mutant protein results in inhibition of the ability of wild-type Dnmt3a and Dnmt3b to methylate DNA in murine ES cells. Furthermore, expression of Dnmt3a R878H in ES cells containing endogenous Dnmt3a or Dnmt3b induces hypomethylation. These results suggest that the DNMT3A R882 mutations, in addition to being hypomorphic, have dominant-negative effects.
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- Authors
- Kim, S. J., Zhao, H., Hardikar, S., Singh, A. K., Goodell, M. A., & Chen, T.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Baylor College of Medicine (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2013-12-12
- Volume
- 122
- Issue
- 25
- Pages
- 4086-4089
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3952368
- OpenAlex
- W2080486691
- Cited by
- 180
- References
- 0
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 15 · 2023: 6 · 2022: 12 · 2021: 15 · 2020: 11 · 2019: 12 · 2018: 14 · 2017: 15 · 2016: 19 · 2015: 19 · 2014: 27
- FWCI
- 15.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research Institute
- Cancer Prevention and Research Institute of Texas
- National Cancer Institute (P30CA016672, P30CA125123)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK092883)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- DNMT3A, acute myeloid leukemia, dominant negative effect, DNA methylation, embryonic stem cells, DNMT3B, hypomethylation, somatic mutations, DNA methyltransferases, catalytic domain
- MeSH terms
- DNA Methyltransferase 3A, DNA Methyltransferase 3B, Animals, Chlorocebus aethiops, DNA (Cytosine-5-)-Methyltransferases, Genes, Dominant, Mice, Mutant Strains, Leukemia, Myeloid, Acute, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Leukemic, DNA Methylation, COS Cells, Amino Acid Substitution, Mutation, Missense, Mice, Embryonic Stem Cells
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