Vitamin B5 and succinyl-CoA improve ineffective erythropoiesis in SF3B1-mutated myelodysplasia
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Syed 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 Bonnet Delphine G Bernard John G Gribben Kevin Rouault-PierreAbstract
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.
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Journal Science Translational Medicine
Volume 15
Issue number 685
Pages eabn5135
Available online
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Publisher website (DOI) 10.1126/scitranslmed.abn5135
Europe PubMed Central 36857430
Pubmed 36857430
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