Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response
Open accessAbstract
Abstract Somatic mutations in DNA Methyltransferase 3A (DNMT3A) are among the most frequent alterations in clonal hematopoiesis (CH) and Acute Myeloid Leukemia (AML), with a hotspot in exon 23 at arginine 882 (DNMT3A-R882). Here we demonstrate that DNMT3A-R882H-dependent CH- and AML cells are specifically susceptible to the hypomethylating agent azacytidine (AZA). Addition of AZA to chemotherapy prolonged AML survival solely in patients with DNMT3A-R882 mutation, suggesting its potential as a novel predictive marker for AZA response. AML and CH mouse models confirmed AZA susceptibility specifically in DNMT3A-R882H-expressing cells. Hematopoietic stem and progenitor cells expressing DNMT3A-R882H exhibited cell-autonomous viral mimicry response as a result of focal DNA hypomethylation at retrotransposon sequences. Administration of AZA boosted hypomethylation of retrotransposons specifically in DNMT3A-R882H expressing cells and maintained elevated levels of canonical interferon-stimulated genes (ISGs), thus leading to suppressed protein translation and increased apoptosis.
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Ccl5 encodes a chemokine that acts on immune cells and neurons and has been associated with brain pathologies, including PD.
“Interestingly though, in particular the MoMg derived from hDNMT3A R882H HSC also prominently expressed Ccl5 , encoding a chemokine that acts on immune cells and neurons, and has been associated with brain pathologies, including PD 53-55 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [53]
The available passages discuss DNMT3A-mutant hematopoietic cells, azacytidine and viral mimicry (Abstract; no page given), not Ccl5’s effects on immune cells or neurons or its association with Parkinson’s disease. Searches for Ccl5 and for the chemokine–Parkinson’s disease connection found no passage addressing the attributed claim. (LLM, conf=0.73)
Experimental — accuracy not yet measuredhDNMT3A R882H monocyte-derived microglia expressed significant levels of Ccl5.
“Notably, hDNMT3A R882H MoMg also expressed significant levels of Ccl5 , a chemokine that has been associated with brain pathologies and was shown to act on immune cells and neurons 53-55 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [53]
The Abstract describes DNMT3A-R882H effects in hematopoietic and leukemia cells, while the other retrieved passages concern methylation and sequencing methods. Searches for Ccl5, monocyte-derived microglia, and brain-related effects found no passage reporting Ccl5 expression in hDNMT3A R882H MoMg. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Cites
Age-related clonal hematopoiesis associated with adverse outcomes
Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., Lindsley, R. C., Mermel, C. H., Burtt, N., Chavez, A., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408617 · Cited by 4,841 · see citing works
Efficacy and safety of low-dose colchicine after myocardial infarction
Tardif, J.-C., Kouz, S., Waters, D. D., Bertrand, O. F., Diaz, R., Maggioni, A. P., Pinto, F. J., Ibrahim, R., Gamra, H., Kiwan, G. S., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1912388 · Cited by 3,159 · see citing works
A decade of exploring the cancer epigenome—biological and translational implications
Baylin, S. B., & Jones, P. A. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3130 · Cited by 2,871 · see citing works
Fenaux, P., Mufti, G. J., Hellstrom-Lindberg, E., Santini, V., Finelli, C., Giagounidis, A., Schoch, R., Gattermann, N., Sanz, G., List, A., et al. (2009) · The Lancet Oncology · doi:10.1016/s1470-2045(09)70003-8 · Cited by 2,663 · cited 1× · see citing works
“Hypomethylating agents (HMAs), such as AZA, represent treat-ment alternatives in elderly individuals with myelodysplastic syndromes and AML who are unfit for aggressive chemotherapy 13–15 .”
Colchicine in Patients with Chronic Coronary Disease
Nidorf, S. M., Fiolet, A. T. L., Mosterd, A., Eikelboom, J. W., Schut, A., Opstal, T. S. J., The, S. H. K., Xu, X.-F., Ireland, M. A., Lenderink, T., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2021372 · Cited by 2,299 · cited 1× · see citing works
“Recently, large randomized clinical trials indicated that anti-inflammatory therapy with either canakinumab or colchicine significantly reduced cardiovascular events in individuals with coronary artery disease 58–60 .”
Chiappinelli, K. B., Strissel, P. L., Desrichard, A., Li, H., Henke, C., Akman, B., Hein, A., Rote, N. S., Cope, L. M., Snyder, A., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.011 · Cited by 2,022 · see citing works
Restoration of p53 function leads to tumour regression in vivo
Ventura, A., Kirsch, D. G., McLaughlin, M. E., Tuveson, D. A., Grimm, J., Lintault, L., Newman, J., Reczek, E. E., Weissleder, R., & Jacks, T. (2007) · Nature · doi:10.1038/nature05541 · Cited by 1,820 · see citing works
Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia
Shlush, L. I., Zandi, S., Mitchell, A., Chen, W. C., Brandwein, J. M., Gupta, V., Kennedy, J. A., Schimmer, A. D., Schuh, A. C., Yee, K. W., et al. (2014) · Nature · doi:10.1038/nature13038 · Cited by 1,443 · see citing works
Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis
McKerrell, T., Park, N., Moreno, T., Grove, C. S., Ponstingl, H., Stephens, J., Crawley, C., Craig, J., Scott, M. A., Hodkinson, C., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.02.005 · Cited by 534 · see citing works
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., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.010 · Cited by 452 · see citing works
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Research works printed but not linked: 3
- Feng, H., Conneely, K.N. & Wu, H. A Bayesian hierarchical model to detect differentially methylated loci from single nucleotide resolution sequencing data. Nucleic Acids Res 42, e69 (2014).
- Zerbino, D.R., Wilder, S.P., Johnson, N., Juettemann, T. & Flicek, P.R. The ensembl regulatory build. Genome Biol 16, 56 (2015).
- Subramanian, A., et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression pro les. Proceedings of the National Academy of Sciences of the United States of America 102, 15545-15550 (2005).
Cited by
Sorted by citations
Clonal hematopoiesis: Mutation-specific adaptation to environmental change
Florez, M. A., Tran, B. T., Wathan, T. K., DeGregori, J., Pietras, E. M., & King, K. Y. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.05.006 · Cited by 129 · see citing works
Kim, 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 · see citing works
Self-citation
- Authors
- Scheller, M., Ludwig, A. K., Göllner, S., Rohde, C., Krämer, S., Stäble, S., Janssen, M., Müller, J.-A., He, L., Bäumer, N., Arnold, C., Gerß, J., Schönung, M., Thiede, C., Niederwieser, C., Niederwieser, D., Serve, H., Berdel, W. E., Thiem, U., Hemmerling, I., Leuschner, F., Plass, C., Schlesner, M., Zaugg, J., Milsom, M. D., Trumpp, A., Pabst, C., Lipka, D. B., & Müller-Tidow, C.
- Affiliations
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- University of Augsburg (DE)
- German Cancer Research Center (DE)
- University Hospital Münster (DE)
- European Molecular Biology Laboratory (DE)
- University of Münster (DE)
- University Hospital Carl Gustav Carus (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- University Hospital Leipzig (DE)
- Goethe University Frankfurt (DE)
- Universität Hamburg (DE)
- Corresponding author
- Scheller, Marina
- ORCID
- Scheller, Marina
- Göllner, Stefanie
- Rohde, Christian
- Krämer, Stephen
- Stäble, Sina
- Janssen, Maike
- He, Lixiazi
- Bäumer, Nicole
- Arnold, Christian
- Gerß, Joachim
- Schönung, Maximilian
- Thiede, Christian
- Niederwieser, Christian
- Niederwieser, Dietger
- Serve, Hubert
- Berdel, Wolfgang E.
- Thiem, Ulrich
- Leuschner, Florian
- Plass, Christoph
- Schlesner, Matthias
- Zaugg, Judith
- Milsom, Michael D.
- Trumpp, Andreas
- Pabst, Caroline
- Lipka, Daniel B.
- Müller-Tidow, Carsten
- Venue
- Nature Cancer
- Published
- 2021-05-25
- Volume
- 2
- Issue
- 5
- Pages
- 527-544
- ISSN
- 2662-1347 (ISSN-L)
- OpenAlex
- W3164869407
- Cited by
- 73
- References
- 10
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 20 · 2023: 7 · 2022: 17 · 2021: 4
- FWCI
- 7.80
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Cancer (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- OPUS (Augsburg University) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (LI 2492/3-1, MU 1328/18‐1)
- Deutsche Krebshilfe (70112974, 70113908)
- Deutsche Jose Carreras Leukämie Stiftung
- 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 › Retinoids in leukemia and cellular processes
- Keywords
- DNMT3A, clonal hematopoiesis, acute myeloid leukemia, azacitidine, hypomethylating agents, interferon-stimulated genes, hematopoietic stem cells, DNA demethylation, predictive biomarkers, apoptosis
- MeSH terms
- Clonal Hematopoiesis, DNA Methyltransferase 3A, Animals, Azacitidine, DNA (Cytosine-5-)-Methyltransferases, Hematopoietic Stem Cells, Mutation, Leukemia, Myeloid, Acute, Mice
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