The objective of this proposal is to identify approaches for targeting mutant HSPC that give rise to clonal hematopoiesis (CH). CH is characterized by selective expansion of hematopoietic stem and progenitor cell (HSPC) clones carrying mutations in genes such as TET2 and DNMT3A. While these clones are nearly ubiquitous at extremely low frequencies in healthy young individuals, CH HSPC expand with age and contribute to aging-related morbidities including increased risk of hematological malignancies, cardiovascular disease (CVD) and all-cause mortality. CH prevalence is particularly elevated individuals with prior genotoxic exposures, smoking history, and/or chronic inflammatory disease. These conditions are associated with chronically perturbed physiological homeostasis, including inflammation and metabolic syndrome. However, the mechanism(s) promoting the selective expansion of hematopoietic stem and progenitor cells (HSPC) harboring CH-associated genetic mutations remains poorly understood. Using the mouse as a model representing key features of human CH, our preliminary data show that CH HSPC exhibit increased levels of the transcription factor Hif-1a, aberrant reductive metabolism and increased ATP production relative to wild-type HSPC. We find that inflammatory cytokines, particularly IL-1b, strongly potentiates CH HSPC expansion, metabolism and Hif-1a activity. For this R56 project, our central hypothesis that CH is the result of an interdependent mechanism in which inflammation potentiates aberrant downstream metabolic activity to support CH HSPC expansion. To address this hypothesis, we propose two specific aims: 1) We will establish and characterize the metabolic features of HSPC in non-conditioned in vivo mouse models of CH, and 2) identify the energy source(s) supporting selective expansion of CH HSPC using functional and metabolomics-based assays. These studies will permit us to identify targetable mechanisms that limit the progression of CH in humans.

R56DK131461

2021-09-21

2022-08-31