Project 1 - Molecular and cellular determinants of hematopoietic clonal expansion

PROJECT SUMMARY The human hematopoietic system is maintained by a pool of hundreds of thousands self-renewing hematopoietic stem cells and multipotent progenitor cells. Recently, large genetic studies have revealed the prevalence of somatic, clonal mutations, in blood cells of healthy individuals, a process referred as clonal hematopoiesis (CH). The mechanisms by which a single hematopoietic cell carrying a CH- related mutation expands at the expense of its normal counterparts is a major question with implications to treat and monitor patients with CH-related complications. Another poorly understood aspect of CH is its incomplete penetrance. While it is speculated that most humans by age 50 will have accumulated one of these mutations in their long-lived hematopoietic progenitors, the degree of clonal expansion among the population is tremendously varied. The cellular and molecular determinants of this range of clonal behaviors are unclear. My lab has utilized high-resolution cellular barcoding technologies to find that hematopoietic progenitor and stem cells exhibit remarkable heterogeneity in their functional response to CH-associated mutations. Our analyses have also identified a number of genes that characterizes the clones exhibiting hyper-competition. Based on these data, our project here aims to understand the molecular mechanisms by which only a subset of hematopoietic progenitors gains and maintains a competitive advantage. Additionally, our approach will take advantage of novel physiologically relevant mouse models of CH where mutations can be directed to stem or progenitor cell compartments. Our efforts here will be facilitated by state-of-the-art genomic and functional tools uniquely suited to characterize heterogeneity at the single cell level. Successful accomplishment of the aims of this project will provide new insight into the mechanisms of clonal dominance in states associated with CH. Finally, our work will potentially identify actionable targets to manipulate clonal competition.