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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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BackgroundAssessment of genetic variant burden in epilepsy-associated brain lesions
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BackgroundEpigenetic regulation of pancreatic adenocarcinoma in the era of cancer immunotherapy
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Berenstein, R., Blau, I. W., Suckert, N., Baldus, C. D., Pezzutto, A., Dörken, B., & Blau, O. (2015) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-015-0173-2 · Cited by 14
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“Substantial overexpression of DNMT3A has been demonstrated in normal karyotype AML (Russler-Germain et al., 2014).”
BackgroundInfluentialTargeted therapy of acute myeloid leukemia
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“DNMT3A establishes de novo DNA methylation, and it is thought that heterozygous mutant DNMT3A acts as a dominant-negative over wild-type DNMT3A, thereby reducing overall methyltransferase activity [49].”
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“Located at the dimer interface, the major DNA binding site, the R882H substitution in DNMT3A disrupts tetramerization and processive catalysis, both of which can be restored by DNA-methyltransferase 3-like (DNMT3L) (26), (27), (28).”
BackgroundThe Roles of DNA Demethylases in Triple-Negative Breast Cancer
Panjarian, S. B., & Issa, J. J. (2021) · Pharmaceuticals · doi:10.3390/ph14070628 · Cited by 13
“Importantly, one could find examples of hypomethylation driving leukemias (DNMT3A mutations) [62] as well as of hypermethylation (IDH mutations) [91] driving the leukemia.”
BackgroundCheng, X., & Blumenthal, R. (2022) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2022.102433 · Cited by 14
Bronzini, I., Aresu, L., Paganin, M., Marchioretto, L., Comazzi, S., Cian, F., Riondato, F., Marconato, L., Martini, V., & Kronnie, G. T. (2016) · Veterinary and Comparative Oncology · doi:10.1111/vco.12231 · Cited by 13
The role of DNA demethylation in induction of stem cells
Ghazimoradi, M. H., & Farivar, S. (2020) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2019.12.005 · Cited by 13
“This phe nomenon rises from role of DNA methylation in gene expression [73-77].”
BackgroundCytosine modifications in myeloid malignancies
Meldi, K. M., & Figueroa, M. E. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.05.002 · Cited by 13
Raj, I. X., Koh, W. K., Harrison, J., Zhang, C. R., Soares, B., Amato, R., Krishnan, A., O’Leary, D. R., Bjeije, H., Parsons, T. M., et al. (2025) · Cell stem cell · doi:10.1016/j.stem.2025.06.010 · Cited by 14
Mack, A., Emperle, M., Schnee, P., Adam, S., Pleiss, J., Bashtrykov, P., & Jeltsch, A. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167482 · Cited by 12
Shabashvili, D. E., Feng, Y., Kaur, P., Venugopal, K., & Guryanova, O. A. (2022) · Experimental Hematology · doi:10.1016/j.exphem.2022.03.008 · Cited by 14
Pathology Consultation on Gene Mutations in Acute Myeloid Leukemia
Ziai, J. M., & Siddon, A. J. (2015) · American Journal of Clinical Pathology · doi:10.1309/ajcp77zfpuqgygwy · Cited by 12
Insights into novel emerging epigenetic drugs in myeloid malignancies
Chandhok, N. S., & Prébet, T. (2019) · Therapeutic Advances in Hematology · doi:10.1177/2040620719866081 · Cited by 11
Clinicopathologic Effect of DNMT3A Mutation in Adult T-Cell Acute Lymphoblastic Leukemia
Aref, S., Menshawy, N. E., El-Ghonemy, M. S., Abouzeid, T., & ElBaiomy, M. A. (2015) · Clinical Lymphoma Myeloma & Leukemia · doi:10.1016/j.clml.2015.11.003 · Cited by 12
Distinct clinical and biological implications of various DNMT3A mutations in myeloid neoplasms
Balasubramanian, S. K., Aly, M. M., Nagata, Y., Bat, T., Przychodzen, B. P., Hirsch, C. M., Ademà, V., Visconte, V., Kuzmanovic, T., Radivoyevitch, T., et al. (2017) · Leukemia · doi:10.1038/leu.2017.295 · Cited by 11
Heiblig, M., Duployez, N., Marceau‐Renaut, A., Lebon, D., Goursaud, L., Plantier, I., Stalnikiewich, L., Cambier, N., Balsat, M., Fossard, G., et al. (2021) · Cancers · doi:10.3390/cancers13092156 · Cited by 11
“Moreover, significant differences in DNA methylation signatures between AML with DNMT3AR882 and non-R882 mutations have been reported, suggesting that mutations in different DNMT3A domains lead to different neomorphic functions [31].”
BackgroundDNMT3A co-mutation in an IDH1-mutant glioblastomaPreprint
Fomchenko, E. I., Erson-Omay, Z., Zhao, A., Bindra, R. S., Huttner, A. J., Fulbright, R. K., & Moliterno, J. A. (2019) · Molecular Case Studies · doi:10.1101/mcs.a004119 · Cited by 11
“The 130-kDa protein product of DNMT3A, a member of the DNA methyltransferase family, is responsible for de novo DNA methylation of cytosine residues within CpG sites independent of DNA replication (Ley et al. 2010; Russler-Germain et al. 2014).”
BackgroundHematopoietic differentiation persists in human iPSCs defective in de novo DNA methylation
Cypris, O., Franzen, J., Frobel, J., Glück, P., Kuo, C., Schmitz, S., Nüchtern, S., Zenke, M., & Wagner, W. (2022) · BMC Biology · doi:10.1186/s12915-022-01343-x · Cited by 10
Clonal hematopoiesis landscape in frequent blood donors
Karpova, D., Encabo, H. H., Donato, E., Calderazzo, S., Scherer, M., Llorian, M., Leppä, A., Würth, R., Stelmach, P., Papazoglou, D., et al. (2025) · Blood · doi:10.1182/blood.2024027999 · Cited by 15
Chen, D. Y., Christopher, M. J., Helton, N., Ferguson, I. M., Ley, T. J., & Spencer, D. H. (2018) · Blood Cancer Journal · doi:10.1038/s41408-018-0072-9 · Cited by 10
Self-citationTan, Y., Liu, H., & Chen, S. (2015) · Frontiers of Medicine · doi:10.1007/s11684-015-0423-x · Cited by 10
“Russler-Germain and coworkers co-expressed the wildtype and R882H-mutated DNMT3A in vitro and found that the enzymatic function of the wild-type DNMT3A was profoundly impaired by its mutated partner, probably via inhibition of tetramerization [61].”
BackgroundEpigenomic Consequences of Coding and Noncoding Driver Mutations
Yao, X., Xing, M., Ooi, W. F., Tan, P. B. O., & Teh, B. T. (2016) · Trends in cancer · doi:10.1016/j.trecan.2016.09.002 · Cited by 10
“DNMT3Amutations, most commonly R882H [34], result in either loss of catalytic activity or DNA binding ability [36].”
Germline DNMT3A mutation in familial acute myeloid leukaemia
Dinardo, C. D., Beird, H. C., Estecio, M. R., Hardikar, S., Takahashi, K., Bannon, S. A., Borthakur, G. M., Jabbour, E. J., Gumbs, C. E., Khoury, J. D., et al. (2020) · Epigenetics · doi:10.1080/15592294.2020.1809871 · Cited by 10
“R882 exerts a disproportionate impact due to dominant-negative activity, leading to a retained DNMT3A wild-type function of only ~20% [13,17].”
BackgroundNam, A. S., Dusaj, N. N., Izzo, F., Murali, R., Myers, R. M., Mouhieddine, T. H., Sotelo, J., Benbarche, S., Waarts, M. R., Gaiti, F., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.01.14.476225 · Cited by 10
Tecik, M., & Adan, A. (2024) · Current Treatment Options in Oncology · doi:10.1007/s11864-024-01202-7 · Cited by 9
Using human disease mutations to understand de novo DNA methyltransferase function
Rolls, W., Wilson, M. D., & Sproul, D. (2024) · Biochemical Society Transactions · doi:10.1042/bst20231017 · Cited by 10
Inside the Battle Against Acute Myeloid Leukemia: Biology, Breakthroughs, and Hope
Bao, J., Freund, O., Sund, L., & Du, W. (2026) · Cells · doi:10.3390/cells15040338 · Cited by 13
Probing altered enzyme activity in the biochemical characterization of cancer
Adam, M. A. A., & Sohl, C. D. (2022) · Bioscience Reports · doi:10.1042/bsr20212002 · Cited by 15
Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway
Palam, L. R., Ramdas, B., Pickerell, K., Pasupuleti, S. K., Kanumuri, R., Cesarano, A., Szymanski, M., Selman, B., Davé, U. P., Sandusky, G. E., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.163864 · Cited by 9
“Results For studies performed here, we used the Mx1-Cre inducible conditional Dnmt3a-KO mouse model, which has been previously described and mimics a significant number of cardinal features seen in mice bearing the R882 mutation, which is considered one of the most common DNMT3A mutations in humans (24, 25).”
MethodTargeting the LSD1/KDM1 Family of Lysine Demethylases in Cancer and Other Human Diseases
Mao, F., & Shi, Y. G. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-38176-8_2 · Cited by 9
Bae, S.-G., Kim, H., Kim, M. Y., Kim, D. H., Shin, S.-I., Ahn, J., & Park, J. (2023) · Molecules and Cells · doi:10.14348/molcells.2023.0093 · Cited by 9
“The most common DNMT3A mutation, R882, blocks tetramer formation and inhibits enzymatic activity (Emperle et al., 2019; Russler-Germain et al., 2014; Yamashi-ta et al., 2010).”
Noncoding rules of survival: epigenetic regulation of normal and malignant hematopoiesis
Wallace, L. M., & Obeng, E. A. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1273046 · Cited by 11
Base Editor Scanning Reveals Activating Mutations of DNMT3A
Garcia, E. M., Lue, N. Z., Liang, J. K., Lieberman, W. K., Hwang, D. D., Woods, J. C., & Liau, B. B. (2023) · ACS Chemical Biology · doi:10.1021/acschembio.3c00257 · Cited by 9
Emerging molecular predictive and prognostic factors in acute myeloid leukemia
McCurdy, S. R., & Levis, M. J. (2017) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2017.1393669 · Cited by 9
“methylation activity [121,122] and lead to specific pat-”
BackgroundTreatments targeting MDS genetics: a fool’s errand?
Dezern, A. E. (2018) · Hematology · doi:10.1182/asheducation-2018.1.277 · Cited by 9
“R882 codon.(27) Mutations in DNMT3A may be associated with a poorer prognosis in MDS but this is inconsistent as paradoxically, DNMT3A mutations may remain during complete remission without adverse outcome.”
BackgroundGuerra-Resendez, R. S., Lydon, S. L., Ma, A. J., Bedford, G. C., Reed, D. R., Kim, S. H., Terán, E. R., Nishiguchi, T., Escobar, M., DiNardo, A. R., et al. (2025) · ACS Synthetic Biology · doi:10.1021/acssynbio.4c00569 · Cited by 8
Tang, J., Ye, X., Xu, Z., Min, T., Tian, Z., Ma, L., He, Y., & Jiang, B. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1672524 · Cited by 8
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Li, Y., Abel, H., Cai, M., LaValle, T. A., Yin, T., Helton, N., Smith, A. M., Miller, C. A., & Ley, T. J. (2024) · Science Advances · doi:10.1126/sciadv.adk8598 · Cited by 8
Self-citation
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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