OVERALL PROJECT SUMMARY Cellular heterogeneity within the hematopoietic stem and progenitor cell (HSPC) pool is an increasingly recognized aspect of normal hematopoiesis. Variability among individual cell clones contributes to these heterogenous cellular states driving diversity of functional outcomes. Each clone bears differences across these functional attributes, which is scripted by the epigenome of each cell. Here, we propose that distinctive clone- specific features are particularly relevant to genetic clonal mutations. Specifically, the cellular and epigenetic state of the clone in which a mutation occurs (the clone-of-origin) will alter cellular outcomes. Further, we hypothesize that clonal diversity may contribute to the highly variable penetrance of a disease phenotype in the context of clonal hematopoiesis (CH). We have assembled four teams of hematopoiesis experts and a pioneering investigator in defining gene regulatory networks utilizing single-cell genomics to address this hypothesis. Using a variety of models, we have evaluated the most common mutations in CH affecting Tet2, Dnmt3a2 and Asxl1. Our motivating hypothesis and these preliminary studies support three focused areas of investigation: 1. Epigenetic states poise the clone-of-origin for transformation by CH mutations, sensitizing cells for clonal dominance; 2. Clones bearing a genetic mutation will exhibit divergent responses to exogenous stimuli further enabling clonal dominance; 3. Metabolic adaptation frequently occur in dominant clones rendering them vulnerable to metabolic drugs to reduce clonal burden. Collectively, these studies will provide a detailed assessment of how hematopoietic clones become dominant, whether molecular signatures can be used to predict clonal behavior in the setting of CH and whether low intensity, metabolism focused strategies can be developed to impair competitively advantaged clones.