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The R882H DNMT3A Mutation Associated with AML Dominantly Inhibits Wild-Type DNMT3A by Blocking Its Ability to Form Active Tetramers
Open accessAbstract
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, 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
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“Furthermore, high-resolution methylation analysis has now shown focal hypomethylation at specific CpG residues in R882mutated patients that is not seen in the non–R882-mutated patients, with a distinct hierarchical clustering of the R882-mutated patients away from the non–R882-mutated patients.(21) Because knowledge o…”
BackgroundOrdering of mutations in acute myeloid leukemia with partial tandem duplication of MLL (MLL-PTD)
Sun, Q.-Y., Ding, L.-W., Tan, K. T., Chien, W., Mayakonda, A., Lin, D.-C., Loh, X.-Y., Xiao, J.-F., Meggendorfer, M., Alpermann, T., et al. (2016) · Leukemia · doi:10.1038/leu.2016.160 · Cited by 87
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“DNMT3AR882 mutations encode a dominant negative protein that reduces the methyltransferase activity of DNMT3A; as a consequence, these AML samples have a focal, canonical hypomethylation phenotype (14, 15).”
BackgroundInfluentialSelf-citationEpigenetics in the hematologic malignancies
Fong, C. Y., Morison, J., & Dawson, M. A. (2014) · Haematologica · doi:10.3324/haematol.2013.092007 · Cited by 87
Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement
Dai, Y., Wang, Y., Huang, J.-Y., Li, X., Shi, X., Xu, J., Lu, J., Su, X., Yang, Y., Zhang, W., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1703476114 · Cited by 82
“In view of the gene transcriptional changes of a large number of pathways, including mTOR in BM cells of Dnmt3a mice and the previous finding that DNMT3A mutations could alter DNA methyltransferase activity (2, 10), we hypothesized that the disturbance in genomic methylation might play a role in causing the aberrant t…”
BackgroundScourzic, L., Couronné, L., Pedersen, M. T., Della-Valle, V., Diop, M. K., Mylonas, E., Calvo, J., Mouly, E., Lopez, C. K., Martin, N., et al. (2016) · Leukemia · doi:10.1038/leu.2016.29 · Cited by 84
Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation
Anteneh, H., Fang, J., & Song, J. (2020) · Nature Communications · doi:10.1038/s41467-020-16213-9 · Cited by 84
Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia
Nwosu, G. O., Ross, D. M., Powell, J. A., & Pitson, S. M. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06810-7 · Cited by 80
“…(FLT3-TKD) [118] DNMT3A 26 Inhibits tetramerization and activity of DNA methyl transferase 3 resulting in hypomethylation of regions of the genome [119] IDH1/IDH2 20 Causes isocitrate dehydrogenases to produce the oncometabolite 2-hydroxyglutatrate [120] resulting in impaired TET2 activity and…”
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“This is consistent with our expectation that individual stable variants exert a more varied impact, with some representing a partial LOF, and others, such as mutations like R882 that result in a dominant-negative effect (8, 9, 19), conferring an even higher fitness advantage (Supplementary Fig.”
BackgroundCui, C., Gan, Y., Gu, L., Wilson, J., Liu, Z., Zhang, B., & Deng, D. (2015) · Genome biology · doi:10.1186/s13059-015-0819-6 · Cited by 77
“The methyltransferase activity of R882H DNMT3A is reduced by approximately 80 % compared with the wide-type [33].”
BackgroundDynamic evolution of clonal epialleles revealed by methclone
Li, S., Garrett-Bakelman, F. E., Perl, A. E., Luger, S. M., Zhang, C., To, B. L., Lewis, I. D., Brown, A. L., D’Andrea, R. J., Ross, M. E., et al. (2014) · Genome biology · doi:10.1186/preaccept-3452801621370693 · Cited by 71
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“DNMT3A mutations outside of the exon 23 hotspot act by distinct mechanisms 9 .”
Patnaik, M. M., Barraco, D., Lasho, T. L., Finke, C. M., Hanson, C. A., Ketterling, R. P., Gangat, N., & Tefferi, A. (2016) · American Journal of Hematology · doi:10.1002/ajh.24581 · Cited by 74
“The Arg882 substitution results in a hypomorphic protein that acts in a dominant negative manner, inhibiting the methyltransferase activity of the remaining wildtype DNMT3A [24].”
BackgroundDNA methyltransferases: emerging targets for the discovery of inhibitors as potent anticancer drugs
Yu, J., Xie, T., Wang, Z., Wang, X., Zeng, S., Kang, Y., & Hou, T. (2019) · Drug Discovery Today · doi:10.1016/j.drudis.2019.08.006 · Cited by 74
Characteristics of DNMT3A mutations in acute myeloid leukemia
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Aging-elevated inflammation promotes DNMT3A R878H-driven clonal hematopoiesis
Liao, M., Chen, R., Yang, Y., He, H., Xu, L., Jiang, Y., Guo, Z., He, W., Jiang, H., & Wang, J. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.09.015 · Cited by 74
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Epigenetics in T‐cell acute lymphoblastic leukemia
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“DNA methylation DNA methylation is executed by the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B, and involves the covalent addition of methyl groups to cytosine in the context of CpG dinucleotides (Fig.”
BackgroundInfluentialDNA methyltransferases in hematological malignancies
Hoang, N.-M., & Rui, L. (2020) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2020.04.006 · Cited by 76
DNA methylation and cancer: transcriptional regulation, prognostic, and therapeutic perspective
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“Generally in most cases mutation in DNMT3AR882H is seen in AML, which causes aberrant DNA methylation [18, 19].”
BackgroundGuryanova, O. A., Lieu, Y. K., Garrett-Bakelman, F. E., Spitzer, B. G., Glass, J. L., SHANK, K. R., Martinez, A. B. V., Rivera, S., Durham, B. H., Rapaport, F., et al. (2015) · Leukemia · doi:10.1038/leu.2015.358 · Cited by 76
“These mutations occur as monoallelic or biallelic nonsense/frameshift alterations, or a dominant-negative R882 substitution 9, 10 .”
DNA methylation and hydroxymethylation in hematologic differentiation and transformation
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Emperle, M., Adam, S., Kunert, S., Dukatz, M., Baude, A., Plass, C., Rathert, P., Bashtrykov, P., & Jeltsch, A. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz911 · Cited by 69
“Previous studies have provided evidence for a dominant negative effect of R882H (21), but this result has remained controversial (19).”
BackgroundThe Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly
Pinese, M., Lacaze, P., Rath, E. M., Stone, A., Brion, M.-J., Ameur, A., Nagpal, S., Puttick, C., Husson, S., Degrave, D., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14079-0 · Cited by 70
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“However, previous studies have shown that normal karyotype DNMT3A R882 mutant AML exhibit focal CpG hypomethylation at sites throughout the genome [31], whereas normal karyotype IDH1 R132 or IDH2 R140 mutant AML exhibit global hyperme-thylation [32].”
Garg, S., Reyes‐Palomares, A., He, L., Bergeron, A., Lavallée, V., Lemieux, S., Gendron, P., Rohde, C., Xia, J., Jagdhane, P., et al. (2019) · Blood · doi:10.1182/blood.2018862383 · Cited by 67
Chaudry, S. F., & Chevassut, T. J. T. (2017) · BioMed Research International · doi:10.1155/2017/5473197 · Cited by 69
“While global hypomethylation of CpG islands and shores has been shown in other studies to be associated with the R882H mutation [81, 96], hypermethylation of CpG promoter regions has also been associated with the samemutation in AML [81, 83].”
BackgroundResultInfluentialLi, J., Sun, C., Cai, W., Li, J., Rosen, B. P., & Chen, J. (2021) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2021.108396 · Cited by 68
Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis
Zioni, N., Bercovich, A. A., Chapal-Ilani, N., Bacharach, T., Rappoport, N., Solomon, A., Avraham, R., Kopitman, E., Porat, Z., Sacma, M., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36906-1 · Cited by 67
Compendium of aberrant DNA methylation and histone modifications in cancer
Hattori, N., & Ushijima, T. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.08.140 · Cited by 66
“When DNMT3A mutation occurs at R882, most frequent in AML, the methyltransferase activity of DNMT3A is decreased [73,74].”
Metadata
- 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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