SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes

SF3B1 is the most frequently mutated RNA splicing factor in multiple neoplasms, including ~25% of myelodysplastic syndromes (MDS) patients. Mortality in MDS frequently results from severe anemia, but the underlying mechanism is largely unknown. Here we elucidate the detailed, elusive pathway by which mutations cause anemia. We demonstrate, in CRISPR-edited cell models, normal human primary cells, and MDS patient cells, that mutant SF3B1 induces a splicing error in transcripts encoding the kinase MAP3K7, resulting in reduced MAP3K7 protein levels and deactivation of downstream target p38 MAPK. We show that disruption of this MAP3K7-p38 MAPK pathway leads to premature downregulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation and apoptosis. As a result, the overproduced, late staged erythroblasts undergo apoptosis and are unable to mature in the bone marrow. Our findings provide a detailed mechanism explaining the origins of anemia in MDS patients harboring mutations.