3094 – ROLE OF BONE MARROW INJURY IN PROMOTING TET2-MEDIATED CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP)

Abstract

CHIP is characterized by selective outgrowth of hematopoietic stem/progenitor cell (HSPC) in the bone marrow (BM) which frequently harbors oncogenic mutations in genes such as TET2. This leads to aberrant expansion of hyperinflammatory immune cells that can contribute to cardiovascular disease and other comorbidities. Prior genotoxic treatments such as chemotherapy and radiation reportedly correlate with the expansion of CHIP mutant HSPC. However, the mechanism(s) remain poorly understood. To address this question, we modeled human CHIP via adoptively transferring Tet2-/- mouse BM into wild-type (WT) recipient mice. In this setting, Tet2-/- HSPC and their progeny preferentially expanded in the BM and blood. Interestingly, Tet2-/- HSPC also colonized non-hematopoietic organs including lung, liver and gonadal adipose tissue. To test whether genotoxic stress caused by radiation accelerated this process, we subjected Tet2-/- CHIP mice to 2.5Gy radiation. Indeed, radiation accelerated Tet2-/- HSPC expansion in nearly all tissues. To assess the impact of microenvironmental factors induced by radiation on CHIP progression, we modeled radiation-induced inflammation and tissue oxygenation using in vitro HSPC culture. Surprisingly, inflammatory cytokines were not sufficient to drive selective expansion of Tet2-/- HSPC. On the other hand, Tet2-/- HSPC displayed a significant proliferative advantage over WT when cultured at high oxygen tension (20%O2) but not in hypoxic conditions representative of healthy BM (1%O2), suggesting high O2 tension caused by BM injury may play a vital role in the selective expansion of Tet2-/- HSPC. Ongoing studies are aimed at understanding the impact of increased oxygen levels in the BM using non-genotoxic approaches and identifying mechanism(s) by which Tet2-/- HSPC harness high O2 tension to proliferate. Such investigations could provide a basis for preventing CHIP and its associated comorbidities.