Txnip Enhances Fitness of Dnmt3a-Mutant Hematopoietic Stem Cells via p21
العنوان: | Txnip Enhances Fitness of Dnmt3a-Mutant Hematopoietic Stem Cells via p21 |
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المؤلفون: | Christine R. Zhang, Elizabeth L. Ostrander, Ostap Kukhar, Cates Mallaney, Jiameng Sun, Emily Haussler, Hamza Celik, Won Kyun Koh, Katherine Y. King, Paul Gontarz, Grant A. Challen |
المصدر: | Blood Cancer Discov |
بيانات النشر: | American Association for Cancer Research (AACR), 2022. |
سنة النشر: | 2022 |
مصطلحات موضوعية: | General Medicine, Hematopoietic Stem Cells, In the Spotlight, DNA Methyltransferase 3A, Clone Cells, Hematopoiesis, embryonic structures, Humans, DNA (Cytosine-5-)-Methyltransferases, Clonal Hematopoiesis, Carrier Proteins, DNA Modification Methylases, Research Articles, Cells, Cultured |
الوصف: | Clonal hematopoiesis (CH) refers to the age-related expansion of specific clones in the blood system, and manifests from somatic mutations acquired in hematopoietic stem cells (HSCs). Most CH variants occur in the gene DNMT3A, but while DNMT3A-mutant CH becomes almost ubiquitous in aging humans, a unifying molecular mechanism to illuminate how DNMT3A-mutant HSCs outcompete their counterparts is lacking. Here, we used interferon gamma (IFNγ) as a model to study the mechanisms by which Dnmt3a mutations increase HSC fitness under hematopoietic stress. We found Dnmt3a-mutant HSCs resist IFNγ-mediated depletion, and IFNγ-signaling is required for clonal expansion of Dnmt3a-mutant HSCs in vivo. Mechanistically, DNA hypomethylation–associated overexpression of Txnip in Dnmt3a-mutant HSCs leads to p53 stabilization and upregulation of p21. This preserves the functional potential of Dnmt3a-mutant HSCs through increased quiescence and resistance to IFNγ-induced apoptosis. These data identify a previously undescribed mechanism to explain increased fitness of DNMT3A-mutant clones under hematopoietic stress. Significance: DNMT3A mutations are common variants in clonal hematopoiesis, and recurrent events in blood cancers. Yet the mechanisms by which these mutations provide hematopoietic stem cells a competitive advantage as a precursor to malignant transformation remain unclear. Here, we use inflammatory stress to uncover molecular mechanisms leading to this fitness advantage. See related commentary by De Dominici and DeGregori, p. 178. This article is highlighted in the In This Issue feature, p. 171 |
تدمد: | 2643-3249 2643-3230 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f2f34e275e4f6572ab893eec9e6bb6c0 https://doi.org/10.1158/2643-3230.bcd-21-0132 |
حقوق: | OPEN |
رقم الأكسشن: | edsair.doi.dedup.....f2f34e275e4f6572ab893eec9e6bb6c0 |
قاعدة البيانات: | OpenAIRE |
تدمد: | 26433249 26433230 |
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