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

Syed A. Mian, Céline Philippe, Eleni Maniati, Pantelitsa Protopapa, Tiffany Bergot, Marion Piganeau, Travis Nemkov, Doriana Di Bella, Valle Morales, Andrew J. Finch, Angelo D'Alessandro, Katiuscia Bianchi, Jun Wang, Paolo Gallipoli, Shahram Kordasti, Anne Sophie Kubasch, Michael Cross, Uwe Platzbecker, Daniel H. Wiseman, Dominique BonnetDelphine G. Bernard, John G. Gribben, Kevin Rouault-Pierre

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


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.

Original languageEnglish
Article numbereabn5135
JournalScience translational medicine
Issue number685
Publication statusPublished - 1 Mar 2023


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