ArticleBlood cancer discovery2022
Txnip Enhances Fitness of Dnmt3a-Mutant Hematopoietic Stem Cells via p21.
Article in Blood cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 21 citations in OpenAlex.
- Tumor microenvironment-mediated hematologic toxicity ofWorld journal of urology · 2026Review
- Clonal hematopoiesis of indeterminate potential (CHIP)-a pivotal contributor of aging and related disorders.Annals of translational medicine · 2026Review
- Inflammageing and clonal haematopoiesis interplay and their impact on human disease.Nature reviews. Molecular cell biology · 2026Review
- Mosaic: Single-Cell Atlas of Stress.Cells · 2026Review
- An inflammatory T-cell-stromal axis contributes to hematopoietic stem/progenitor cell failure and clonal evolution in human myelodysplastic syndrome.Nature communications · 2025Article
- Parallel Evolution of Leukemic Clones in Myeloproliferative Neoplasms.Research square · 2025Article
- Article
- Non-canonical functions of DNMT3A in hematopoietic stem cells regulate telomerase activity and genome integrity.Cell stem cell · 2025Article
- Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.Nature communications · 2025Article
- Geroscience in heart failure: the search for therapeutic targets in the shared pathobiology of human aging and heart failure.The journal of cardiovascular aging · 2025Article
- BIRC5 upregulation enhances DNMT3A-mutant T-ALL cell survival and pathogenesis.Blood neoplasia · 2024Article
- Hematopoietic aging promotes cancer by fueling IL-1⍺-driven emergency myelopoiesis.Science (New York, N.Y.) · 2024Article
- Review
- Regulators of clonal hematopoiesis and physiological consequences of this condition.The journal of cardiovascular aging · 2024Article
- Inactivation of p53 provides a competitive advantage to del(5q) myelodysplastic syndrome hematopoietic stem cells during inflammation.Haematologica · 2023Article
- The impact of epigenetic modifications on allogeneic hematopoietic stem cell transplantation.Frontiers in immunology · 2023Review
- Comprehensive comparison of gene expression diversity among a variety of human stem cells.NAR genomics and bioinformatics · 2022Article
- Clonal hematopoiesis: Mutation-specific adaptation to environmental change.Cell stem cell · 2022Review
- Dnmt3a-Mutant Hematopoietic Stem Cell Rewire IFNγ Signaling to Gain Clonal Advantage.Blood cancer discovery · 2022Article
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.