Inflammatory Bowel Disease-induced Inflammation Augments Clonal Hematopoiesis of Indeterminate Potential through Ref-1

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by age-related somatic mutations in hematopoietic stem and progenitor cells (HSC/Ps) and is correlated with an increased risk of myeloid malignancies, elevated inflammatory pathways in circulating myeloid cells, higher all-cause mortality, chronic kidney disease, and cardiovascular disease. The pathophysiology of inflammatory bowel disease (IBD) is intrinsically linked to heightened inflammation. Nevertheless, the presence of CHIP in IBD and its role in the pathophysiology of IBD remains poorly elucidated. In the UK Biobank, CHIP was associated with an increased incidence of IBD. Females with CHIP had a 1.33-fold higher risk, which was further validated in All of Us data base (ßOR = 1.29). For Crohn's disease, DNMT3A mutations conferred a 1.81-fold increased incidence in females compared to non-DNMT3A-carriers, which rose to 2.09 for large clones (variant allele fraction ≥10%). In contrast, for ulcerative colitis, TET2 large clones were significantly associated, and only among individuals under 45. These associations were further identified using two-sample Mendelian randomization. In a mouse model of CHIP-IBD, HSC/Ps with Dnmt3a mutation demonstrated significantly worse pathophysiology compared to controls, due in part to heightened expression of Apurinic/apyrimidinic endonuclease 1 (APE1) in the bone marrow and colon. Treatment with the APE1/Ref-1 inhibitor APX3330 ameliorated CHIP-IBD driven by the Dnmt3a mutation.