Vitamin B5 and succinyl-CoA improve ineffective erythropoiesis in SF3B1 mutated myelodysplasia

Patients with myelodysplastic syndrome and ring sideroblasts (MDS-RS) present with symptomatic anemia due to ineffective erythropoiesis that impede their quality of life and increase morbidity. More than 80% of patients with MDS-RS harbor splicing factor 3B subunit 1 (SF3B1) mutations, the founder aberration driving MDS-RS disease. Here, we report how mis-splicing of coenzyme A synthase (COASY), induced by mutations in SF3B1, impacts heme biosynthesis and erythropoiesis. Our data revealed that COASY was upregulated during normal erythroid differentiation, and its silencing prevented the formation of erythroid colonies, impeded erythroid differentiation, and precluded heme accumulation. In patients with MDS-RS, loss of protein due to COASY mis-splicing led to depletion of both CoA and succinyl-CoA. Notably, supplementation with COASY substrate (vitamin B5) rescued CoA and succinyl-CoA concentrations in SF3B1(mut) cells and mended erythropoiesis differentiation defects in MDS-RS primary patient cells. Our findings reveal a key role of the coenzyme A synthesis pathway in erythroid maturation and identify upstream as well as downstream metabolites of COASY as a potential treatment for anemia in patients with MDS-RS.