Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFN gamma signaling

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 IFN gamma alone was sufficient to phenocopy CH by Dnmt3a(-/-) HSCs upon infection. Transcriptional and epigenetic profiling and functional studies indicate reduced differentiation associated with widespread methylation alterations, and reduced secondary stress-induced apoptosis accounts for Dnmt3a(-/-) clonal expansion during infection. DNMT3A mutant human HSCs similarly exhibit defective IFN gamma-induced differentiation. We thus demonstrate that IFN gamma signaling induced during chronic infection can drive DNMT3A-loss-of-function CH.