SHMT2-Folate-Folate Receptor Axis Impaired Erythropoiesis in Myelodysplastic Syndrome

Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal bone marrow diseases with a high risk of progressing to acute myeloid leukemia. Current therapies for MDS patients include bone marrow transplantation and hypomethylation chemotherapy, however, since MDS is very common in elderly people, many patients cannot tolerate transplantation related complications or acquire drug resistance, making it urgent to develop novel therapy. Abnormal metabolic regulation had been reported to be involved the pathogenesis of many diseases including MDS, but the underlying mechanisms are not fully characterized.

To explore underlying mechanisms and develop novel therapy to treat MDS, we utilized NUP98-HOXD13 knock-in mice which was a well-known MDS mouse model. We purified bone marrow lineage negative cells from MDS and control mice and performed RNA sequencing. After data processing, we found SHMT2 was dramatically up regulated in MDS mice. SHMT2 involved the one-carbon unit cycling and regulated the contents of glycine, serine and folate. Followed metabolomic profiling showed that, only folate, but not glycine and serine, was significantly increased in MDS mice. Furthermore, SHMT2 expression and folate were also significantly increased in MDS patients compared to the healthy cases. These findings indicated that increased SHMT2 expression and overloaded folate may involve MDS pathogenesis. Indeed, high folate diet or folate intraperitoneal injection decreased red blood cell (RBC) number and hemoglobin content, inhibited bone marrow erythropoiesis and shortened the survival of wild mice. And folate intraperitoneal injection into the MDS mice exacerbated anemia symptom. More importantly, using the CRISPR/Cas9 technique and bone marrow transplantation assay, we found that knock-out SHMT2 in MDS mice decreased folate content and alleviated MDS phenotypes. Through a series of assays, we further found that high dose of folate binds to folate receptor 2 (FOLR2) and leads its translocation from membrane to nucleus where FOLR2 regulated gene expression as a transcription factor. FOLR2 up-regulated IRF2 and IRF2BP2 expression levels and inhibited normal erythropoiesis.

Taken together, our findings demonstrated that SHMT2-folate-folate receptor axis inhibited erythropoiesis in MDS, and targeting SHMT2 had therapeutic effectiveness for MDS treatment. Our findings also provided more comprehensive understanding on the relationship between folate and erythropoiesis.

No relevant conflicts of interest to declare.