uNDERSTANDING AND TARGETING SENESCENCE IN CLONAL HEMATOPOIESIS

Clonal hematopoiesis (CH) is characterized by the presence of hematopoietic cells carrying one or more somatic mutations in the absence of overt hematological disease. The prevalence of CH rises with age and has been associated with increased mortality and a higher risk of progression to hematological cancers, as well as agerelated conditions such as cardiovascular and pulmonary events and liver disease. However, the mechanisms underlying the promotion of CH and its connection to age-related sequelae are not fully understood. A prominent feature of aging is the accumulation of senescent cells. Cellular senescence represents a stress response program marked by a halt in proliferation and the release of a proinflammatory Senescence-Associated Secretory Phenotype (SASP). Under normal circumstances, the SASP attracts immune cells, targeting senescent cells and restoring tissue homeostasis. However, increased tissue damage and declining immune function impede this clearance during aging, resulting in a chronic pro-inflammatory milieu. Evidence suggests chronic inflammation promotes CH and alters the balance between quiescence, self-renewal, and lineage commitment in hematopoietic stem and progenitor cells (HSPCs). Preliminary data from our research indicates that CH-mutant clones heavily rely on proinflammatory cytokines, and in aged animal models, they aggregate near senescent cells. The goal of my KOO postdoctoral work is to elucidate the role of cellular senescence in the progression of CH. I aim to explore the interactions between senescent cells and CH-mutant clones and identify key signaling molecules that could be potential biomarkers for disease progression in aging. Additionally, I will utilize uPAR-CAR T cells to eliminate senescent cells and study how this affects CH expansion, thus interrogating the therapeutic potential of targeting senescence to prevent high-risk CH. In conclusion, completing my proposed work will yield new insights into the age-driven progression of CH, as well as the development of novel biomarkers and therapeutic strategies from a senolytic angle.