3001 – STRESS-SPECIFIC ERYTHROID PROGENITORS IN REGENERATIVE ERYTHROPOIESIS AND MYELOPROLIFERATIVE NEOPLASM

Regenerative erythropoiesis is critical for the recovery from surgery, chemotherapy, bone marrow transplantation and infection. We identified a new erythroid progenitor with colony-forming unit-erythroid (CFU-E) activity, which we named stress CFU-E (sCFU-E). sCFU-E cells are targets of erythropoietin (Epo) and its receptor EpoR, are only expanded in erythroid stress, and are essential for the recovery of erythrocyte numbers in regenerative erythropoiesis. Interestingly, in myeloproliferative neoplasms (MPN), sCFU-E are hijacked by the oncogenic JAK2 mutant, JAK2(V617F), to drive constitutive EpoR signaling and overproduction of erythrocytes.

Mechanistically, Epo promotes sCFU-E expansion through the JAK2-STAT5 pathway by inducing the expression of IRS2, thereby engaging pro-growth signaling from the IGF1 receptor (IGF1R). Inhibition of IGF1R/IRS2 signaling impairs sCFU-E cell growth, whereas exogenous IRS2 expression rescues cell growth in sCFU-E expressing truncated EpoR with defective STAT5 activation. Inability to expand sCFU-E cells by truncated EpoR protects against JAK2(V617F)-driven erythrocytosis in mice. In samples from MPN patients, the number of sCFU-E-like cells increases, and inhibition of IGR1R/IRS2 signaling blocks Epo-hypersensitive erythroid cell colony formation. Moreover, metabolomics analyses showed that sCFU-E accumulates high levels of ascorbate (vitamin C), and ascorbate accelerates sCFU-E differentiation independent of its function as an antioxidant. Epo regulates sCFU-E differentiation by inducing the expression of SLC23A2, an ascorbate transporter.

Our discovery and analysis of a novel stress-specific erythroid progenitor cell population, which connects regenerative erythropoiesis with pathogenic erythrocytosis, could offer valuable insights for developing new treatments for both anemia and MPN.