The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers
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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.
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Dnmt3a loss of function mutations comprise the majority of human clonal hematopoiesis-associated mutations.
“Dnmt3a loss of function mutations, which comprise the majority of human CH-associated mutations (Russler-Germain et al., 2014)”
From Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling (2021) · cites this paper as Russler-Germain et al., 2014
The Discussion describes DNMT3A mutations that impair its function, and the Introduction reports DNMT3A mutation frequencies in acute myeloid leukemia (AML). Neither passage establishes that DNMT3A loss-of-function mutations comprise the majority of mutations associated with human clonal hematopoiesis; the reported population is AML, not clonal hematopoiesis. (LLM, conf=0.83)
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- Authors
- Russler-Germain, D. A., Spencer, D. H., Young, M. A., Lamprecht, T. L., Miller, C. A., Fulton, R., Meyer, M. R., Erdmann-Gilmore, P., Townsend, R. R., Wilson, R. K., & Ley, T. J.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Ley, Timothy J.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 25
- Issue
- 4
- Pages
- 442-454
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4018976
- OpenAlex
- W2025193307
- Cited by
- 452
- References
- 37
- Citations by year
- 2026: 23 · 2025: 24 · 2024: 37 · 2023: 30 · 2022: 34 · 2021: 47 · 2020: 39 · 2019: 33 · 2018: 36 · 2017: 43 · 2016: 49 · 2015: 34 · 2014: 23
- FWCI
- 35.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Washington
- National Institutes of Health (UL1TR000448)
- National Heart, Lung, and Blood Institute (T32HL007088)
- National Cancer Institute (CA162086, CA101937, R01CA162086, P01CA101937, P30CA091842)
- National Institute of General Medical Sciences (P41GM103422)
- National Center for Advancing Translational Sciences
- 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, de novo DNA methyltransferases, DNA methylation, CpG hypomethylation, somatic mutations, enzyme inhibition
- MeSH terms
- DNA Methyltransferase 3A, Alleles, Amino Acid Sequence, DNA (Cytosine-5-)-Methyltransferases, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Prognosis, Protein Conformation, Leukemia, Myeloid, Acute, DNA Methylation
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