Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 15, Issue 685, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abn5135
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Patients with myelodysplastic syndrome and ring sideroblasts (MDS-RS) suffer from symptomatic anemia due to ineffective erythropoiesis caused by SF3B1 mutations. Mis-splicing of COASY induced by these mutations affects heme biosynthesis and erythropoiesis. Supplementation with COASY substrate may serve as a potential treatment for anemia in MDS-RS patients.
Patients with myelodysplastic syndrome and ring sideroblasts (MDS-RS) present with symptomatic anemia due to ineffective erythropoiesis that impedes their quality of life and increases morbidity. More than 80% of pa-tients 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, affects heme biosynthesis and erythropoiesis. Our data revealed that COASY was up-regulated 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. Supplementation with COASY substrate (vitamin B5) rescued CoA and succinyl-CoA concentrations in SF3B1mut cells and mended erythropoiesis differentiation defects in MDS-RS primary patient cells. Our findings reveal a key role of the COASY pathway in erythroid mat-uration and identify upstream and downstream metabolites of COASY as a potential treatment for anemia in patients with MDS-RS.
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