Early drivers of clonal hematopoiesis shape the evolutionary trajectories of acute myeloid leukemia.

Mutations commonly found in AML such as , and can be found in the peripheral blood of otherwise healthy adults - a phenomenon referred to as clonal hematopoiesis (CH). These mutations are thought to represent the earliest genetic events in the evolution of AML. Genomic studies on samples acquired at diagnosis, remission, and at relapse have demonstrated significant stability of CH mutations following induction chemotherapy. Meanwhile, later mutations in genes such as and , have been shown to contract at remission and in the case of often are absent at relapse. We sought to understand how early CH mutations influence subsequent evolutionary trajectories throughout remission and relapse in response to induction chemotherapy. Here, we assembled a retrospective cohort of patients diagnosed with AML at our institution that underwent genomic sequencing at diagnosis as well as at the time of remission and/or relapse (total n = 182 patients). Corroborating prior studies, and mutations were generally eliminated at the time of cytologic complete remission but subsequently reemerged upon relapse, whereas , and mutations often persisted through remission. Early CH-related mutations exhibited distinct constellations of co-occurring genetic alterations, with and mutations enriched in AML, while and mutations were enriched in and AML, respectively. In the case of and mutations, these differences vanished at the time of complete remission yet readily reemerged upon relapse, indicating the reproducible nature of these genetic interactions. Thus, early CH-associated mutations that precede malignant transformation subsequently shape the evolutionary trajectories of AML through diagnosis, therapy, and relapse.