Abstract 018: TET2 Loss of Function-driven Clonal Hematopoiesis Promotes Age-related Vascular and Systemic Inflammation and Metabolic Dysfunction in Mice

Abstract

Background: Acquired mutations in the hematopoietic system and subsequent clonal hematopoiesis are emerging as potential new drivers of atherosclerotic cardiovascular disease. TET2 was the first gene reported to exhibit acquired mutations in blood cells of cancer-free elderly individuals and we recently reported that the clonal expansion of TET2-mutant hematopoietic cells accelerates atherogenesis in mouse models by exacerbating inflammatory responses in the atherosclerotic plaque. The objective of this study was to examine whether TET2 loss of function-driven clonal hematopoiesis also has systemic effects on age-related inflammation and metabolic function beyond its direct actions on the plaque. Methods: An adoptive transfer technique was used to introduce a small percentage of Tet2-/- hematopoietic cells in non-irradiated C57Bl/6J mice, which were monitored for 16 months following transfer. Flow cytometry techniques were used to follow the expansion of Tet2-/- cells in the blood. Results: Tet2-/- hematopoietic cells expanded progressively over time after adoptive transfer, with a mild myeloid bias. This was paralleled by increased expression of the pro-inflammatory cytokines IL-1β and IL-6 in the white adipose tissue and the aortic wall, as well as by increased serum levels of IL-6. Tet2-/- expansion also led to exacerbated systemic insulin resistance, as revealed by insulin tolerance tests. Conclusion: TET2-deficient hematopoietic cell expansion promotes vascular and systemic inflammation, as well as metabolic dysfunction in aging mice. These results support a causal role for TET2 mutation-driven clonal hematopoiesis in age-related cardiometabolic disease, and suggest that somatic TET2 mutations may contribute to atherosclerosis by promoting inflammation both systemically and locally in the atherosclerotic plaque.