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

Sci Transl Med. 2023 Mar;15(685):eabn5135. doi: 10.1126/scitranslmed.abn5135. Epub 2023 Mar 1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia*
  • Erythropoiesis
  • Heme
  • Humans
  • Myelodysplastic Syndromes*
  • Pantothenic Acid
  • Phosphoproteins
  • Quality of Life
  • RNA Splicing Factors
  • Transcription Factors

Substances

  • succinyl-coenzyme A
  • Pantothenic Acid
  • Transcription Factors
  • Heme
  • SF3B1 protein, human
  • RNA Splicing Factors
  • Phosphoproteins