TY - JOUR
T1 - Vitamin B5 and succinyl-CoA improve ineffective erythropoiesis in SF3B1-mutated myelodysplasia
AU - Mian, Syed A
AU - Philippe, Céline
AU - Maniati, Eleni
AU - Protopapa, Pantelitsa
AU - Bergot, Tiffany
AU - Piganeau, Marion
AU - Nemkov, Travis
AU - Di Bella, Doriana
AU - Morales, Valle
AU - Finch, Andrew J
AU - D'Alessandro, Angelo
AU - Bianchi, Katiuscia
AU - Wang, Jun
AU - Gallipoli, Paolo
AU - Kordasti, Shahram
AU - Kubasch, Anne Sophie
AU - Cross, Michael
AU - Platzbecker, Uwe
AU - Wiseman, Daniel H
AU - Bonnet, Dominique
AU - Bernard, Delphine G
AU - Gribben, John G
AU - Rouault-Pierre, Kevin
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
KW - Humans
KW - Erythropoiesis
KW - Pantothenic Acid
KW - Quality of Life
KW - Anemia
KW - Transcription Factors
KW - Myelodysplastic Syndromes
KW - Heme
KW - RNA Splicing Factors
KW - Phosphoproteins
UR - https://www.scopus.com/pages/publications/85149427744
U2 - 10.1126/scitranslmed.abn5135
DO - 10.1126/scitranslmed.abn5135
M3 - Article
C2 - 36857430
SN - 1946-6234
VL - 15
SP - eabn5135
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 685
ER -