SUMMARY The accumulation of somatic DNA mutations in driver genes within the hematopoietic system can provide a fitness advantage to the mutant cell and thus allow for its clonal expansion. This process is referred to as clonal hematopoiesis and leads to a situation where a substantial fraction of an individual’s blood cells are replaced by clones with the driver gene mutation. Previous large exome sequencing studies in humans have shown that these somatic mutations accumulate during aging and are associated with a higher rate of cardiovascular-related deaths. Moreover, recent experimental studies support the idea that clonal hematopoiesis causally promotes cardiovascular disease (CVD). More recently, genotoxic stresses such as radiation or chemotherapy have also been shown to facilitate hematopoietic clonal expansion in cancer patients. Compared with age-related clonal hematopoiesis that is mediated primarily by mutations in epigenetic regulators such as DNMT3A and TET2, clonal hematopoiesis resulting from prior exposure to cytotoxic therapy is uniquely associated with high frequencies of mutations in TP53 and PPM1D. This clonal selection/expansion of TP53 and PPM1D mutant clones by cancer therapy may subsequently increase the risk of CVD, and addressing this clinically-relevant question represents the main objective of the current proposal. In fact, over the past decade, the number of cancer survivors has grown, thus there has been a paradigm shift in the approach to survivor care with a renewed focus on maximizing non-cancer-related outcomes, such as CVD. Therefore, there is an unmet need to understand the potential connection between cancer-therapy related clonal hematopoiesis and CVD. Thus, this study aims to examine whether a causal connection exists between therapy-related clonal hematopoiesis and chemotherapy-associated cardiomyopathy. As a proof-of-concept, I will test the hypothesis that TP53- and PPM1D-mediated clonal hematopoiesis contributes to anthracycline-induced cardiomyopathy using sophisticated animal models.