IFNg Signaling is a Driver of Dnmt3a-Mutant Clonal Hematopoiesis

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 acquisition of a mutation and CH, suggesting that environmental factors contribute to clonal expansion. We used a murine model to investigate the prediction that infection provides selective pressure favoring expansion of Dnmt3a-mutant hematopoietic stem cells (HSCs). We created Dnmt3a mosaic mice by transplanting a mixed population of Dnmt3a-mutant and WT HSCs into WT mice and observed substantial expansion of Dnmt3a-mutant HSCs during chronic mycobacterial infection. Transcriptional profiling and functional studies indicate reduced differentiation and reduced secondary stress-induced apoptosis account for Dnmt3a-mutant clonal expansion during infection. Both injection of recombinant IFNγ alone and infecting mice transplanted with HSCs lacking the differentiation factor Batf2 partially phenocopied CH by Dnmt3a-mutant HSCs upon infection. This is the first study demonstrating that IFNγ signaling induced during chronic infection can drive DNMT3A-mutant CH.