Our research examines the mechanisms underlying the origins of early-onset blood cancers in children and young adults, with a focus on myeloid malignancies arising in the context of germline leukemia predisposition conditions such as GATA2 deficiency and RUNX1-familial platelet disorder. A central theme across our work is clonal hematopoiesis (CH), the pre-malignant expansion of mutant blood stem cells that precedes transformation to overt malignancy. We investigate the origins and drivers of CH across distinct contexts: in patients with germline predisposition syndromes, in donor cells transmitted through stem cell transplantation, and in neonates who carry pre-leukemic fusion genes in utero. By identifying the factors that promote clonal expansion and malignant transformation, our goal is to better predict, prevent, and intervene in blood cancers before they fully develop.