: 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 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, 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 maturation and identify upstream and downstream metabolites of COASY as a potential treatment for anemia in patients with MDS-RS.
Vitamin B5 and succinyl-CoA improve ineffective erythropoiesis in SF3B1-mutated myelodysplasia / Mian, Syed A; Philippe, Céline; Maniati, Eleni; Protopapa, Pantelitsa; Bergot, Tiffany; Piganeau, Marion; Nemkov, Travis; Di Bella, Doriana; Morales, Valle; Finch, Andrew J; D'Alessandro, Angelo; Bianchi, Katiuscia; Wang, Jun; Gallipoli, Paolo; Kordasti, Shahram; Kubasch, Anne Sophie; Cross, Michael; Platzbecker, Uwe; Wiseman, Daniel H; Bonnet, Dominique; Bernard, Delphine G; Gribben, John G; Rouault-Pierre, Kevin. - In: SCIENCE TRANSLATIONAL MEDICINE. - ISSN 1946-6242. - 15:685(2023), p. eabn5135. [10.1126/scitranslmed.abn5135]