Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis

All dividing cells require the essential vitamin folate. Hematopoietic cells harbor a unique sensitivity to folate deprivation, as implied by the development of folate-deficient anemia and the utility of anti-folate chemotherapy in blood cancer. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines, as well as primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis that is followed by enhanced heme metabolism, hemoglobin synthesis and erythroid differentiation. This finding is phenocopied by inhibition of folate metabolism using SHIN1, an inhibitor of the folate enzymes SHMT1/2. The metabolically-driven differentiation is rescued by supplementation of purine precursors, yet occurs independent of nucleotide sensing through mTORC1 and AMPK. Our work profiles the metabolic response to folate depletion in erythroid cells and suggest that premature differentiation of folate-deprived erythroid progenitor cells is a mechanistic etiology to folate-deficiency induced anemia.