m6A-driven SF3B1 translation control steers splicing to direct genome integrity and leukemogenesis_Ciesla_et_al

SF3B1 is the most mutated splicing factor (SF) in myelodysplastic syndromes (MDS), clonal hematopoietic disorders with variable risk of leukemic transformation. Although tumorigenic SF3B1 mutations have been extensively characterized, the role of “non-mutated” SF3B1 in cancer remains largely unresolved. Here we identify a conserved epitranscriptomic program that steers SF3B1 levels to counteract leukemogenesis. Our analysis of human and murine pre-leukemic MDS cells reveals dynamic regulation of SF3B1 protein abundance, which impacts MDS-to-leukemia progression in vivo. Mechanistically, ALKBH5-driven 5’UTR m6A demethylation fine-tunes SF3B1 translation directing splicing of central DNA repair and epigenetic regulators during transformation. This impacts genome stability and leukemia progression in vivo, supporting integrative analysis in humans that SF3B1 molecular signatures may predict mutational variability and poor prognosis. These findings highlight a post-transcriptional gene expression nexus that unveils unanticipated SF3B1-dependent cancer vulnerabilities.