LAUSR

Significance Myelodysplastic syndromes (MDS) are the most commonly diagnosed malignancy of the elderly in the United States, but what causes severe anemia in MDS has been unknown. Our findings provide a detailed mechanism underlying the origins of severe anemia and other cardinal phenotypes in MDS patients harboring SF3B1 mutations, which are found in about a quarter of all MDS patients. In addition, we define a role of MAP3K7 and a MAP3K7-p38 MAPK axis in human terminal erythroid differentiation and created a SF3B1 cell model that recapitulates many of the terminal erythroid differentiation events of mutant SF3B1 MDS patients, which should prove valuable for developing novel drugs and therapies. SF3B1 is the most frequently mutated RNA splicing factor in cancer, including in ∼25% of myelodysplastic syndromes (MDS) patients. SF3B1-mutated MDS, which is strongly associated with ringed sideroblast morphology, is characterized by ineffective erythropoiesis, leading to severe, often fatal anemia. However, functional evidence linking SF3B1 mutations to the anemia described in MDS patients harboring this genetic aberration is weak, and the underlying mechanism is completely unknown. Using isogenic SF3B1 WT and mutant cell lines, normal human CD34 cells, and MDS patient cells, we define a previously unrecognized role of the kinase MAP3K7, encoded by a known mutant SF3B1-targeted transcript, in controlling proper terminal erythroid differentiation, and show how MAP3K7 missplicing leads to the anemia characteristic of SF3B1-mutated MDS, although not to ringed sideroblast formation. We found that p38 MAPK is deactivated in SF3B1 mutant isogenic and patient cells and that MAP3K7 is an upstream positive effector of p38 MAPK. We demonstrate that disruption of this MAP3K7-p38 MAPK pathway leads to premature down-regulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation, erythroid hyperplasia, and ultimately apoptosis. Our findings thus define the mechanism leading to the severe anemia found in MDS patients harboring SF3B1 mutations.