Project 2 - Cell of origin contributions and vulnerabilities in clonal hematopoiesis

Project Summary Heterogeneity within the hematopoietic stem cell (HSC) compartment is well defined and we hypothesize may contribute to the wide range of phenotypes emerging from initiation of clonal hematopoiesis (CH). This project will use distinctive tools for assessing cell state in the context of Tet2 deletion to determine how the epigenetic and transcriptional program of the cell of origin affects clonal dominance. These data will provide insight into the mechanisms of clonal dominance and may offer epigenetic signatures indicative of risk for subsequent validation. We will also focus on the metabolic state of dominant CH to define whether features of those cells render them vulnerable to low intensity intervention. Successful accomplishment will guide strategies for selective depletion of aberrant dominant clones.