American Association for Cancer Research
Browse
bcd-21-0132_supplementary_figures_suppsf1-sf7.pdf (3.01 MB)

Supplementary Figure from Txnip Enhances Fitness of Dnmt3a-Mutant Hematopoietic Stem Cells via p21

Download (3.01 MB)
journal contribution
posted on 2023-04-04, 01:24 authored by 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
Supplementary Figure from Txnip Enhances Fitness of Dnmt3a-Mutant Hematopoietic Stem Cells via p21

Funding

NCI

NIH

ICTS

CTSA

History

ARTICLE 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. 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

Usage metrics

    Blood Cancer Discovery

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC