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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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The R736H cancer mutation in DNMT3A modulates the properties of the FF-subunit interface
Kunert, S., Emperle, M., Adam, S., Bräcker, J., Brockmeyer, J., Rajavelu, A., & Jeltsch, A. (2022) · Biochimie · doi:10.1016/j.biochi.2022.12.005 · Cited by 2
Meirson, T., Bomze, D., Schueler‐Furman, O., Stemmer, S. M., & Markel, G. (2023) · NAR Cancer · doi:10.1093/narcan/zcac040 · Cited by 2
“In contrast, examples of LoF driver mutations in tumor suppressors arising in rigid elements, such as -helix, include DNMT3AR882H that disrupts WT tetramers leading to reduced methyltransferase activity (43), whereas PTENR130G losses phosphatase activity while maintaining dimerization with WT, which constrains its pho…”
BackgroundCase report: biallelic DNMT3A mutations in acute myeloid leukemia
Cumbo, C., Orsini, P., Anelli, L., Zagaria, A., Iannò, M. F., Cecco, L. D., Minervini, C. F., Coccaro, N., Tota, G., Parciante, E., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1205220 · Cited by 3
“DNMT3A R882 and non-R882 patients are considered distinct entities with different genomic and clinical features (19, 20).”
BackgroundClonal evolution in leukemia: preleukemia, evolutionary models, and clinical implications
He, X., Xia, M.-F., Teng, J.-Y., Zhou, B. S., & Wang, Q. (2023) · Genome Instability & Disease · doi:10.1007/s42764-023-00104-6 · Cited by 3
Asfa, S., Bonab, R. A., Önder, O., Uca, M., Döşeme, H., Küçük, C., Georgakilas, A. G., Stadler, B. M., Logotheti, S., Kale, S., et al. (2024) · Cancers · doi:10.3390/cancers16213607 · Cited by 2
Reframing thalassaemia syndrome as a benign haematopoietic stem cell disorder
Maggio, A., Napolitano, M., Taher, A. T., Bou‐Fakhredin, R., & Ostuni, M. A. (2024) · British Journal of Haematology · doi:10.1111/bjh.19919 · Cited by 3
“60 Similarly, mutations in isocitrate dehydrogenase 1 (IDH1) and its mitochondrial homologue isocitrate dehydrogenase 2 (IDH2) lead to reduced levels of α - ketoglutarate, resulting in hypermethylated histones at promoter regions.”
Kramer, M. H., Richardson, S. N., Li, Y., Yin, T.-K., Helton, N. M., George, D. R., Cai, M., Ramakrishnan, S. M., Katerndahl, C., Miller, C. A., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci195929 · Cited by 2
Self-citationMalignant Transformation and Epigenetics
Han, Y., Ren, J., Yu, W., Terashima, M., & Muegge, K. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-800957-4.00007-2 · Cited by 2
Bagacean, C., Bordron, A., Tempescul, A., Ianotto, J., Guillerm, G., Brooks, W. H., Couturier, M., Zdrenghea, M., Berthou, C., & Renaudineau, Y. (2018) · OBM Genetics · doi:10.21926/obm.genet.1804054 · Cited by 2
Shen, F., Zhao, Y., Yu, X., Wang, B.-L., Wu, X., Lan, G., & Gao, R. (2021) · Chinese Journal of Integrative Medicine · doi:10.1007/s11655-021-3316-7 · Cited by 2
Cancer Stem Cells and the Development of Cancer
Ghoneim, N. I., Mohamed, R. H., Gamal, A., Magdy, S., & El‐Badri, N. (2020) · Learning materials in biosciences · doi:10.1007/978-3-030-55359-3_5 · Cited by 2
The Medical Genome Reference Bank: Whole genomes and phenotype of 2,570 healthy elderlyPreprint
Pinese, M., Lacaze, P. A., Rath, E. M., Stone, A. M., Brion, M., Ameur, A., Nagpal, S., Puttick, C., Husson, S., Degrave, D., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/473348 · Cited by 2
“gain-of-function missense variants in JAK2 V617F (9 individuals), NRAS G12D (1), a dominant negative allele in DNMT3A, R882H (1) (Russler-Germain et al., 2014), and a putative loss-of-function variant in TP53, C275Y (1).”
BackgroundPavlović, S., & Tos̆ić, N. (2019) · Europeanization and globalization · doi:10.1007/978-3-030-16465-2_28 · Cited by 1
Genomic Landscape and Risk Stratification of Acute Myeloid Leukemia
Hou, H. (2023) · Springer eBooks · doi:10.1007/978-981-99-3810-0_5 · Cited by 1
Metformin modulates mitochondrial metabolism and epigenetic dysregulation in DNMT3A-mutated clones
Hu, X.-Y., Wang, B., & Zhang, L. (2025) · Molecular Biomedicine · doi:10.1186/s43556-025-00311-5 · Cited by 1
“DNMT3A (DNA Methyltransferase 3 A), which is important for adding methyl groups to DNA, is one of the most commonly mutated genes in CH [3].”
Simonson, M. W., Mitra, S., Tay, J. H., Wang, W., & Maier, A. B. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103259 · Cited by 1
Heterozygous Dnmt3a R878C induces expansion of quiescent hematopoietic stem cell pool
Higo, T., Suzuki, Y., Sato, M., Koya, J., Mizuno, H., Miyauchi, M., Masamoto, Y., Kataoka, K., Sumitomo, Y., Tsuruta-Kishino, T., et al. (2022) · Experimental Hematology · doi:10.1016/j.exphem.2022.02.006 · Cited by 3
Sanyal, T., Das, A., Bhowmick, P., & Bhattacharjee, P. (2022) · The Nucleus · doi:10.1007/s13237-022-00392-5 · Cited by 1
DNMT3A Co-Mutation with SF3B1, ASXL1 and TET2 in Indian Patients with Myelodysplastic Syndrome (MDS)
Beevi, S. S., Yadav, R., Verma, V. K., Darapuneni, R. C., Reddy, S. G., Paduval, S., Sadawarte, S., & Jayashanker, D. (2022) · Biochemistry and Molecular Biology · doi:10.11648/j.bmb.20220701.11 · Cited by 1
WT1 and DNMT3A Mutations in Prognostic Significance of Acute Myeloid Leukemia: A Meta-Analysis
Ma, S., Tang, L., Tang, H. J., Wu, C., Pu, X., Yang, J., & Niu, N. (2024) · Cancer Biotherapy and Radiopharmaceuticals · doi:10.1089/cbr.2024.0093 · Cited by 1
“36 There is a dispute on the effect of this mutation on the clinical outcome in people with AML.”
Transcriptomic changes including p53 dysregulation prime DNMT3A mutant cells for transformation
Lawrence, E., Cooray, A., Kueh, A. J., Pál, M., Tai, L., Garnham, A. L., Suen, C. S. N. L. W., Vanyai, H. K., Gouil, Q. A., Lancaster, J., et al. (2025) · EMBO Reports · doi:10.1038/s44319-025-00450-4 · Cited by 1
“Some groups proposed that mutant DNMTA R882 acts in a dominant negative manner (Kim et al, 2013; Russler-Germain et al, 2014), whereas others suggested that the hotspot mutation may alter the fl anking sequence preference of DNMT3A (Emperle et al, 2019; Emperle et al, 2018).”
Chatzikalil, E., Asvestas, D., Tzeis, S. E., & Solomou, E. E. (2025) · Diagnostics · doi:10.3390/diagnostics15151915 · Cited by 1
“They also increase CXCL chemokine expression and activate pathways like RASSF1A-ERK1/2 in hematopoietic stem and progenitor cells, which can contribute to myocardial fibrosis [121–123].”
Genetic Aspects of Hematopoietic Malignancies
Kelley, T. W., & Patel, J. L. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-816061-9.00008-4 · Cited by 1
Heiblig, M., Labussière, H., Larcher, M. V., Fossard, G., Balsat, M., Ducastelle, S., Loron, S., Hayette, S., Huet, S., Sujobert, P., et al. (2020) · Blood · doi:10.1182/blood-2020-141890 · Cited by 1
Funata, S., Fukayama, M., & Kaneda, A. (2016) · Encyclopedia of Life Sciences · doi:10.1002/9780470015902.a0026465 · Cited by 1
Lee, D., Koo, B., Kim, S., Byun, J., Hong, J., Shin, D., Sun, C.-H., Song, J., Kim, J., Jaiswal, S., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.13.528223 · Cited by 1
“Finally, variants were post-filtered to avoid false positive calls using the following criteria: (1) variants 448 should be present with variant allele frequency greater than 5%, (2) variant alleles should be supported by at least five 449 sequencing reads, (3) variants should not be present with ExAC population allel…”
MethodGenetic landscape of DNMT3A R882H reveals mechanism of aberrant oligomerizationPreprint
Garcia, E. M., Lavidor, O. R., Raval, S., Lue, N. Z., Liang, J. K., McFadden, M., Hwang, D. D., Zepeda, M. L., Chen, L. W., Carr, S. A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.24.678339 · Cited by 2
Pershad, Y., Zhao, K., Amburg, J. C. V., Corty, R. W., Parker, A., Silver, A. J., Almadani, Y. F., Kishtagari, A., Hodges, E. C., Savona, M. R., et al. (2026) · medRxiv · doi:10.64898/2026.04.03.26350108 · Cited by 1
A WIMSical approach to decoding DNA methylation in myeloid leukemia
Guryanova, O. A., & Levine, R. L. (2014) · Genome biology · doi:10.1186/s13059-014-0441-z
“DNMT3A is directly involved in the establishment and maintenance of DNA methylation patterns, and DNMT3A mutant AML patient-derived samples show a small but significant decrease in mean methylation relative to nonmutated samples [10].”
BackgroundComputational Biology-Driven Genomic and Epigenomic Delineation of Acute Myeloid Leukemia
Sanders, M. A. (2015) · EUR Research Repository (Erasmus University Rotterdam)
Ultra-Deep Sequencing of Bisulfite-Modified DNA
Qin, T., Park, Y., Figueroa, M. E., & Sartor, M. A. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-800140-0.00003-0
Maretty, L., Sibbesen, J. A., & Krogh, A. (2014)
Evidences of a cytotoxic activity of S-adenosylmethionine on OCI-AML3 cellsPreprint
von Hohenstaufen, K. A., Puoti, I., Méloni, M., & Servi, B. D. (2014) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/004978
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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