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

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 SF3B1 mut 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.

Red Blood Cell Metabolism In Vivo and In Vitro

“…When considering erythropoiesis, one-carbon metabolism is one of the first pathways that is referenced. Folates and methyl group donors such as methionine, choline and betaine—along with B6, B12 and B5 cofactors [ 80 , 81 ]—are essential for de novo purine nucleotide synthesis to support proliferation, as well as for generating glycine to contribute to heme synthesis described above. However, methyl-group donors also participate in RBC redox homeostasis and its dysregulation, such as in the context of folate dietary deficiency or excess [ 81 ].…”

Engineering oncogenic hotspot mutations onSF3B1via CRISPR-directed PRECIS mutagenesis

“…The lack of proper isogenic models is attributable to several factors, with one key culprit being the limitations of current site-specific mutagenesis methods. Most SF3B1 mutant cell lines are engineered via CRISPR-Cas9 or AAV technologies [3][4][5]17,18 . Both approaches utilize homology-directed repair (HDR) to insert the K700E mutation into SF3B1, which relies on cell's intrinsic DNA repair capacity for efficient editing and underlies the limited availability of SF3B1 mutant cell lines.…”