Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling.

ABSTRACT: Age-related clonal hematopoiesis (CH) is a risk factor for malignancy, cardiovascular disease, and all-cause mortality. Somatic mutations in DNMT3A are drivers of CH, but decades may elapse between the acquisition of a mutation and CH, suggesting that environmental factors contribute to clonal expansion. We tested whether infection provides selective pressure favoring the expansion of Dnmt3a mutant hematopoietic stem cells (HSCs) in mouse chimeras. We created Dnmt3a-mosaic mice by transplanting Dnmt3a^-/- and WT HSCs into WT mice and observed the substantial expansion of Dnmt3a^-/- HSCs during chronic mycobacterial infection. Injection of recombinant IFNγ alone was sufficient to phenocopy CH by Dnmt3a^-/- HSCs upon infection. Transcriptional and epigenetic pro

SUBMITTER: Hormaechea-Agulla D 

PROVIDER: S-EPMC8349829 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature