Yan, B.; Yuan, Q.; Kaur, P.; Mckee, A. R.; Shabashvili, D. E.; Guryanova, O. A.

Clonal hematopoiesis (CH) is associated with an increased risk of non-hematologic chronic diseases including metabolic disorders, yet the causality remains poorly defined. DNMT3A is the most frequently altered gene in CH, commonly through monoallelic loss-of-function (LOF) and Arg882His (RH) hotspot mutations. Here we demonstrate in a mouse model that CH driven by Dnmt3a RH and especially LOF promotes obesity, diabetes, and chronic liver disease, further exacerbated by high-fat diet (HFD).