IFNγ Signaling is a Driver of Dnmt3a-Mutant Clonal Hematopoiesis

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.

Keywords: clonal hematopoiesis, infection, interferon gamma, Dnmt3a, clonal competition

Suggested Citation: Suggested Citation

Hormaechea Agulla, Daniel and Matatall, Katie A. and Le, Duy T. and Kain, Bailee and Long, Xiaochen and Kus, Pawel and Jaksik, Roman and Challen, Grant A. and Kimmel, Marek and King, Katherine Y., IFNγ Signaling is a Driver of Dnmt3a-Mutant Clonal Hematopoiesis. Available at SSRN: https://ssrn.com/abstract=3564993 or http://dx.doi.org/10.2139/ssrn.3564993

This version of the paper has not been formally peer reviewed.