The FOLR2-IRF2BP2 axis mediates erythropoiesis impairment by excess folic acid in myelodysplastic neoplasms.

Myelodysplastic neoplasms (MDS) are a group of heterogeneous clonal hematopoietic disorders with a high risk of progression to acute myeloid leukemia. Despite folic acid being an essential vitamin for human development that can be harmful at high levels, it is still unclear how its excess precisely impacts erythropoiesis in MDS patients. Based on non-targeted metabolomics, we identified significantly elevated folic acid levels in both MDS mice and MDS patients. Functional studies revealed that an excess folic acid diet exacerbated anemia in MDS mice, while restricted folic acid intake alleviated disease phenotypes. Mechanistically, excess folic acid promotes the nuclear translocation of FOLR2, which functions as a transcription factor to bind the promoter of IRF2BP2 and drive its expression. Upregulated IRF2BP2 subsequently represses key erythroid transcription factors GATA1 and KLF1, leading to erythroid differentiation arrest. The folic acid-FOLR2-IRF2BP2 axis is upregulated, and high IRF2BP2 expression correlates with poor prognosis in MDS patients. Our study unveils a novel pathological role of folic acid in promoting MDS progression by disrupting hematopoietic stem/progenitor cells and impairing erythropoiesis, suggesting dietary folic acid restriction and targeting FOLR2-IRF2BP2 axis as potential therapeutic strategies. The FOLR2-IRF2BP2 Axis Mediates Erythropoiesis Impairment by Excess Folic Acid in Myelodysplastic Syndromes. In NUP98-HOXD13 transgenic/MDS mice, folic acid content was significantly increased. Excess folic acid diet exacerbated disease symptoms in MDS mice. Reducing folic acid intake significantly alleviated MDS symptoms. Mechanistically, excess folic acid not only promoted the expansion of hematopoietic stem progenitor cells but also disrupted erythropoiesis involving the FOLR2-IRF2BP2 pathway.