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Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response

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 (DNMT3AR882). Here, we demonstrate that DNMT3AR882H-dependent CH and AML cells are specifically susc...

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Main Authors: Scheller, Marina (Author) , Ludwig, Anne Kathrin (Author) , Göllner, Stefanie (Author) , Rohde, Christian (Author) , Krämer, Stephen (Author) , Stäble, Sina (Author) , Janssen, Maike (Author) , Müller, James-Arne (Author) , He, Lixiazi (Author) , Bäumer, Nicole (Author) , Arnold, Christian (Author) , Gerß, Joachim (Author) , Schönung, Maximilian (Author) , Thiede, Christian (Author) , Niederwieser, Christian (Author) , Niederwieser, Dietger (Author) , Serve, Hubert (Author) , Berdel, Wolfgang E. (Author) , Thiem, Ulrich (Author) , Hemmerling, Inga (Author) , Leuschner, Florian (Author) , Plass, Christoph (Author) , Schlesner, Matthias (Author) , Zaugg, Judith B. (Author) , Milsom, Michael (Author) , Trumpp, Andreas (Author) , Pabst, Caroline (Author) , Lipka, Daniel (Author) , Müller-Tidow, Carsten (Author)
Format: Article (Journal)
Language:English
Published: 25 May 2021
In: Nature cancer
Year: 2021, Volume: 2, Issue: 5, Pages: 527-544
ISSN:2662-1347
DOI:10.1038/s43018-021-00213-9
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s43018-021-00213-9
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s43018-021-00213-9
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Author Notes:Marina Scheller, Anne Kathrin Ludwig, Stefanie Göllner, Christian Rohde, Stephen Krämer, Sina Stäble, Maike Janssen, James-Arne Müller, Lixiazi He, Nicole Bäumer, Christian Arnold, Joachim Gerß, Maximilian Schönung, Christian Thiede, Christian Niederwieser, Dietger Niederwieser, Hubert Serve, Wolfgang E. Berdel, Ulrich Thiem, Inga Hemmerling, Florian Leuschner, Christoph Plass, Matthias Schlesner, Judith Zaugg, Michael D. Milsom, Andreas Trumpp, Caroline Pabst, Daniel B. Lipka, Carsten Müller-Tidow
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Summary: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 (DNMT3AR882). Here, we demonstrate that DNMT3AR882H-dependent CH and AML cells are specifically susceptible to the hypomethylating agent azacytidine (AZA). Addition of AZA to chemotherapy prolonged AML survival solely in individuals with DNMT3AR882 mutations, suggesting its potential as a predictive marker for AZA response. AML and CH mouse models confirmed AZA susceptibility specifically in DNMT3AR882H-expressing cells. Hematopoietic stem cells (HSCs) and progenitor cells expressing DNMT3AR882H 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 DNMT3AR882H-expressing cells and maintained elevated levels of canonical interferon-stimulated genes (ISGs), thus leading to suppressed protein translation and increased apoptosis.
Item Description:Gesehen am 31.08.2023
Physical Description:Online Resource
ISSN:2662-1347
DOI:10.1038/s43018-021-00213-9

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