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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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Epigenetic therapies in acute myeloid leukemia: where to from here?
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Ilyas, A. M., Ahmad, S., Faheem, M., Naseer, M. I., Kumosani, T., Al-Qahtani, M. H., Gari, M. A., & Ahmed, F. (2015) · BMC Genomics · doi:10.1186/1471-2164-16-s1-s5 · Cited by 55
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“Recent reports describe DNMT3A mutations to be present in preleukaemic HSCs that are capable of surviving chemotherapy and persisting in remission samples (Corces-Zimmerman et al, 2014; Shlush et al, 2014).”
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“Although DNMT3A-R882 mutations are almost always heterozygous, the mutant protein was proposed to exert a dominant-negative effect by dimerizing with its wild-type counterpart and preventing formation of the more active tetrameric complex (25, 36), although this has been disputed (37).”
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“Recent publications indicated that this mutation influences the tetramer formation of Dnmt3a (41, 42).”
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“(Arg882His) variant leads to approximately an 80% reduction of methyltransferase activity when compared to the wild-type protein (Russler-Germain et al., 2014).”
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“to interact with wild-type Dnmt3A and Dnmt3B in a dominant negative manner inhibiting the wild-type methyltransferase activity of the tetrameric complex.(8,11)”
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“R882H DNMT3A mutant was shown to have reduced methyltransferase activity and also to dominant-negatively inhibit wildtype DNMT3A by interference with homotetramer formation.(31) DNMT3A and TET2 mutations were sometimes seen together in AITL(32) as well as in myeloid malignancies, although the epigenetic effects were o…”
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Nicholson, T. B., Veland, N., & Chen, T. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-800206-3.00003-3 · Cited by 49
The DNMT3A R882H mutant displays altered flanking sequence preferences
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“Fortuitously, the discoveries of the importance of proteins such as TET2 and DNMT3A have come at a time when our capacity to identify DNA methylation modifications at base-pair resolution has been enormously facilitated by a dramatic drop in the cost of high-throughput sequencing.”
BackgroundInfluentialPathogenesis of Myeloproliferative Disorders
Nangalia, J., Grinfeld, J., & Green, A. R. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044454 · Cited by 48
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“The most common mutation is R882H, that has been proven to act as a dominant-negative on the wild-type DNMT3A [41–43], losing the ability to form homotetramers [41,43] and thus reducing the methytransferase activity (Table 2, Figure 2).”
BackgroundMutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia
Coombs, C. C., Sallman, D. A., Devlin, S. M., Dixit, S., Mohanty, A. S., Knapp, K. M., Ali, N. H. A., Lancet, J. E., List, A. F., Komrokji, R. S., et al. (2016) · Haematologica · doi:10.3324/haematol.2016.148999 · Cited by 41
“Overall rate of CR 23% 43% 28% (CR+CRi) Median/mean Median: 2 (1-23) Median: 4 (1-12) Median: 3 (1-23) number of HMA Mean: 4.”
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“Arg882His DNMT3A mutation has been extensively studied in the field of AML research [Russler-Germain et al., 2014] and has been shown to reduce methyltransferase activity by dominantly inhibiting wild-type DNMT3A by blocking its ability to form active tetramers [Russler-Germain et al.”
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“DNMT3A contains a C-terminal catalytic methyl-transferase structural domain and two known regulatory structural domains [57].”
BackgroundPML-RARA requires DNA methyltransferase 3A to initiate acute promyelocytic leukemia
Cole, C. B., Verdoni, A. M., Ketkar, S., Leight, E. R., Russler‐Germain, D. A., Westover, T., Demeter, R., Magrini, V. J., & Ley, T. J. (2015) · Journal of Clinical Investigation · doi:10.1172/jci82897 · Cited by 41
Self-citationClonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications
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DNA methylation in normal and malignant hematopoiesis
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“This mutation acts as a dominant negative resulting in reduced catalytic activity [30, 31].”
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“Malignant cells from cancer patients carrying this mutation display hypomethylation patterns at differentiallymethylated regions (DMRs), although total genomic CpG methylation is nearly unchanged relative to WT cells (17, 18).”
BackgroundInfluentialNew preclinical models for angioimmunoblastic T-cell lymphoma: filling the GAP
Mhaidly, R., Krug, A., Gaulard, P., Lemonnier, F., Ricci, J., & Verhoeyen, E. (2020) · Oncogenesis · doi:10.1038/s41389-020-00259-x · Cited by 39
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“Consistent with the interference of 2-HG on histone methylation, strong activity of the DOT1L (disruptor of telo- meric silencing 1-like) inhibitor EPZ004777 was reported against primary IDH1/2 mutated AML cells in vitro (Sarkaria et al, 2014).”
BackgroundPathogenic Mechanisms in Acute Myeloid Leukemia
Chakraborty, S., & Park, C. Y. (2022) · Current Treatment Options in Oncology · doi:10.1007/s11864-022-01021-8 · Cited by 36
Ketkar, S., Verdoni, A. M., Smith, A. M., Bangert, C. V., Leight, E. R., Chen, D. Y., Brune, M. K., Helton, N. M., Hoock, M., George, D. R., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1918611117 · Cited by 35
“Although many of these DMRs are located within or near genes, very few closely linked genes have been found to be differentially expressed (13, 14).”
InfluentialSelf-citationPrognostic impact of DNMT3A mutation in acute myeloid leukemia with mutated NPM1
Oñate, G., Bataller, Á., Garrido, A., Hoyos, M., Arnán, M., Vives, S., Coll, R., Tormo, M., Sampol, A., Escoda, L., et al. (2021) · Blood Advances · doi:10.1182/bloodadvances.2020004136 · Cited by 37
New insights in the pathogenesis of T-cell lymphomas
Lemonnier, F., Gaulard, P., & de Leval, L. (2018) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000474 · Cited by 35
“sequences of the genes, with few hotspots, such as the dominant-negative DNMT3A mutant (20).”
BackgroundGebhard, C., Glatz, D., Schwarzfischer, L., Wimmer, J., Stasik, S., Nuetzel, M., Heudobler, D., Andreesen, R., Ehninger, G., Thiede, C., et al. (2018) · Leukemia · doi:10.1038/s41375-018-0165-2 · Cited by 34
“It is known that patients harboring CEBPA mutations show better overall survival [7, 12, 62–68], while DNMT3A mutations correlate with worse prognosis [9, 51].”
BackgroundKim, J.-S., Trzebanski, S., Shin, S.-H., Schori, L., Frumer Friedman, G. R., Ilani, N. C., Kadam, A., Vicario, R., Aust, O., Bugaeva, P., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115609 · Cited by 33
Hollink, I. H. I. M., van den Ouweland, A. M. W., Beverloo, H. B., Arentsen-Peters, S. T. C. J. M., Zwaan, C. M., & Wagner, A. (2017) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2017-104574 · Cited by 35
Haney, S. L., Upchurch, G. M., Opavska, J., Klinkebiel, D. L., Hlady, R. A., Suresh, A., Pirruccello, S. J., Shukla, V., Lu, R., Costinean, S., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.004 · Cited by 33
“DNMT3A R882H mutants show both decreased methyltransferase activity (Russler-Germain et al., 2014) and dominant negative functions as its overexpression results in hypomethylation (Kim et al., 2013).”
BackgroundFocal disruption of DNA methylation dynamics at enhancers in IDH-mutant AML cells
Wilson, E. R., Helton, N., Heath, S. E., Fulton, R. S., Payton, J. E., Welch, J. S., Walter, M. J., Westervelt, P., DiPersio, J. F., Link, D. C., et al. (2021) · Leukemia · doi:10.1038/s41375-021-01476-y · Cited by 31
“DNA hypermethylation in IDH AML cells requires DNMT3A To assess whether de novo DNA methylation by DNMT3A contributes to IDH-associated hypermethylation, we analyzed methylation levels at IDH-specific DMRs in seven AML samples with co-occurring IDH1 (N= 5) or IDH2 (N= 2) and DNMT3A mutations (R882 mutations have a mor…”
Self-citationEmperle, M., Dukatz, M., Kunert, S., Holzer, K., Rajavelu, A., Jurkowska, R. Z., & Jeltsch, A. (2018) · Scientific Reports · doi:10.1038/s41598-018-31635-8 · Cited by 34
“Previous work has reported that formation of mixed wildtype/R882H complexes leads to a strong loss of catalytic activity observed in in vitro DNA methylation assays (Russler-Germain et al., 2014, Cancer Cell 25:442–454).”
BackgroundResultInfluentialSomatic alterations and dysregulation of epigenetic modifiers in cancers
Aumann, S., & Abdel-Wahab, O. I. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.08.004 · Cited by 31
“functional tetramers, which are required for maximal de novo methylation activity [9].”
BackgroundMisregulation of the expression and activity of DNA methyltransferases in cancer
Mensah, I. K., Norvil, A. B., AlAbdi, L., McGovern, S. E., Petell, C. J., He, M., & Gowher, H. (2021) · NAR Cancer · doi:10.1093/narcan/zcab045 · Cited by 36
“Through its interaction with the WT enzyme, the Arg882His variant is suggested to have a dominant-negative effect on cooperativity (103,122,125).”
BackgroundLu, R., Wang, J., Ren, Z., Yin, J., Wang, Y., Cai, L., & Wang, G. G. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-3275 · Cited by 31
“Furthermore, the dominant-negative effect was proposed for DNMT3A (29, 31).”
InfluentialStudy on the Immune Escape Mechanism of Acute Myeloid Leukemia With DNMT3A Mutation
Que, Y., Li, H., Lin, L., Zhu, X., Xiao, M., Wang, Y., Zhu, L., & Li, D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.653030 · Cited by 30
“The mutated proteins can interact with normal proteins to form dysfunctional tetramers, and thus change the pattern of genomemethylation (5).”
BackgroundJawad, M. D., Afkhami, M., Ding, Y., Zhang, X., Li, P., Young, K., Xu, M. L., Cui, W., Zhao, Y., Halene, S., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.849376 · Cited by 29
“NS Poor-very poor 13/54 (24%) 13/58 (22%) Average VAF% 27 (2-49) 28 (5-66) NS”
BackgroundInfluentialEpigenetic dysregulation of hematopoietic stem cells and preleukemic state
Kunimoto, H., & Nakajima, H. (2017) · International Journal of Hematology · doi:10.1007/s12185-017-2257-6 · Cited by 30
Beard, D. C., Zhang, X., Wu, D. Y., Martin, J. R., Erickson, A., Boua, J.-V. K., Hamagami, N., Swift, R. G., McCullough, K. B., Ge, X., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113411 · Cited by 33
“25 Differences in allele severity are further reflected by the increased number of DMRs in the R878H mutant compared to the P900L mutant, and we demonstrate that these methylation differences overlap key genomic regulatory elements such as gene bodies and enhancers.”
Haney, S. L., Hlady, R. A., Opavska, J., Klinkebiel, D. L., Pirruccello, S. J., Dutta, S., Datta, K., Simpson, M. A., Wu, L., & Opavský, R. (2015) · Oncogene · doi:10.1038/onc.2014.472 · Cited by 29
Epigenomics-Guided Drug Development: Recent Advances in Solving the Cancer Treatment “jigsaw puzzle”
Dzobo, K. (2019) · OMICS A Journal of Integrative Biology · doi:10.1089/omi.2018.0206 · Cited by 29
“Mutations in DNMT3A are also known to be involved in acute myeloid leukemia (AML) disease progression (Russler-Germain et al., 2014; Shivarov et al., 2013; Yang et al., 2015).”
The acute myeloid leukemia variant DNMT3A Arg882His is a DNMT3B-like enzyme
Norvil, A. B., AlAbdi, L., Liu, B., Tu, Y. H., Forstoffer, N. E., Michie, A. R., Chen, T., & Gowher, H. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa139 · Cited by 28
“the dominant negative activity of this variant (26,27).”
BackgroundResultInfluentialMurine models of clonal haematopoiesis to assess mechanisms of cardiovascular disease
Wang, Y., Sano, S., Ogawa, H., Horitani, K., Evans, M. A., Yura, Y., Miura‐Yura, E., Doviak, H., & Walsh, K. X. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab215 · Cited by 26
Decoding DNA methylation in epigenetics of multiple myeloma
Yang, T., Liu, X., Kumar, S. K., Jin, F., & Dai, Y. (2021) · Blood Reviews · doi:10.1016/j.blre.2021.100872 · Cited by 28
The genetic basis of human height
Bicknell, L. S., Hirschhorn, J. N., & Savarirayan, R. (2025) · Nature Reviews Genetics · doi:10.1038/s41576-025-00834-1 · Cited by 30
“This observation is consistent with at least half of the ~80% heritability of height seen in many studies being explained by common genetic variation.”
Jeltsch, A., Adam, S., Dukatz, M., Emperle, M., & Bashtrykov, P. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167186 · Cited by 28
Epidemiology and Pathogenesis of Myelodysplastic Syndrome
Rotter, L. K., Shimony, S. O., Ling, K., Chen, E., Shallis, R. M., Zeidan, A. M., & Stahl, M. F. (2023) · The Cancer Journal · doi:10.1097/ppo.0000000000000665 · Cited by 27
Translation of Epigenetics in Cell-Free DNA Liquid Biopsy Technology and Precision Oncology
Tan, W. Y., Nagabhyrava, S., Ang-Olson, O., Das, P., Ladel, L., Sailo, B., He, L., Sharma, A. R., & Ahuja, N. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46070390 · Cited by 28
“For example, approximately 50% of the DNMT3A mutations occur in the catalytic domain at position R882 (most commonly R882H) [85,86].”
BackgroundWalsh, K. X., Raghavachari, N., Kerr, C. L., Bick, A. G., Cummings, S. R., Druley, T. E., Dunbar, C. E., Genovese, G., Goodell, M. A., Jaiswal, S., et al. (2022) · Frontiers in Aging · doi:10.3389/fragi.2022.841796 · Cited by 29
Characterizing crosstalk in epigenetic signaling to understand disease physiology
Lempiäinen, J. K., & Garcia, B. A. (2023) · Biochemical Journal · doi:10.1042/bcj20220550 · Cited by 29
Epigenetic Regulations in Mammalian Cells: Roles and Profiling Techniques
Kim, U., & Lee, D.-S. (2023) · Molecules and Cells · doi:10.14348/molcells.2023.0013 · Cited by 27
Norvil, A. B., Petell, C. J., AlAbdi, L., Wu, L., Rossie, S. S., & Gowher, H. (2016) · Biochemistry · doi:10.1021/acs.biochem.6b00964 · Cited by 27
The Role of Somatic Mutations in Acute Myeloid Leukemia PathogenesisPreprint
Kishtagari, A., & Levine, R. L. (2020) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a034975 · Cited by 26
“The recurrent mutation at codon R882 is the most frequent DNMT3Amutation in AML patients, the resultant protein exerts a dominant-negative effect on wild-type DNMT3A methyltransferase activity (HolzSchietinger et al. 2012; Cancer GenomeAtlas Research et al. 2013; Russler-Germain et al. 2014).”
BackgroundNovel epigenetic therapies in hematological malignancies: Current status and beyond
Gallipoli, P., & Huntly, B. J. P. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.07.005 · Cited by 25
“The mutations are usually hemizygous and are predicted to result in loss of or an alteration of the function of the native protein, with the most frequent mutation found in humans (R882H) appearing to act as a dominant negative [37, 38].”
BackgroundTang, S., Shen, H., Mao, X., Dai, H., Zhu, X., Xue, S., Ding, Z., Lu, J., Wu, D., & Tang, X. (2017) · International Journal of Hematology · doi:10.1007/s12185-017-2256-7 · Cited by 25
Kumar, D., Mehta, A., Panigrahi, M. K., Nath, S., & Saikia, K. K. (2017) · Hematology/Oncology and Stem Cell Therapy · doi:10.1016/j.hemonc.2017.09.004 · Cited by 27
miR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2
Fuentes‐Mattei, E., Bayraktar, R., Manshouri, T., Silva, A. M., Ivan, C., Gulei, D., Fabris, L., do Amaral, N. S., Mur, P., Perez, C., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.121781 · Cited by 25
“In vitro experiments indicate that the DNMT3AR882C mutation acts in a dominant negative manner to disrupt the de novo methyltransferase activity of wild-type homotetramers (70).”
BackgroundBera, R., Chiu, M.-C., Huang, Y., Liang, D., Lee, Y., & Shih, L. (2018) · Neoplasia · doi:10.1016/j.neo.2018.08.013 · Cited by 27
A novel class of selective non-nucleoside inhibitors of human DNA methyltransferase 3A
Huang, S., Stillson, N. J., Sandoval, J. E., Yung, C., & Reich, N. O. (2021) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2021.127908 · Cited by 24
Liao, M., Dong, Q., Chen, R., Xu, L., Jiang, Y., Guo, Z., Xiao, M., He, W., Cao, C., Hu, R., et al. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00697-5 · Cited by 25
“DNMT3A is one of the de novo DNA methyltransferases, and DNMT3A R882H AML cells exhibit decreased de novo methyltransferase activity and markedly hypomethylation throughout the genomes of these cells at specific CpGs [7].”
BackgroundBäumer, N., Scheller, A., Wittmann, L., Faust, A., Apel, M., Nimmagadda, S. C., Geyer, C., Grunert, K., Kellmann, N., Peipp, M., et al. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01390-5 · Cited by 24
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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