MYELOID NEOPLASIA Critical requirement for Stat5 in a mouse model of polycythemia vera

The JAK2V617F mutation has been identi-fied in most cases of Ph-negative my-eloproliferative neoplasms (MPNs) in-cluding polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofi-brosis (PMF). Expression of JAK2V617F results in constitutive activation of mul-tiple signaling molecules/pathways. How-ever, the key signaling downstream of JAK2V617F required for transformation and induction of MPNs remains elusive. Using a mouse genetic strategy, we show here that Stat5 is absolutely required for the pathogenesis of PV induced by Jak2V617F. Whereas expression of Jak2V617F in mice resulted in all the features of human PV, including an in-crease in red blood cells, hemoglobin, hematocrit, white blood cells, platelets, and splenomegaly, deletion of Stat5 in the Jak2V617F knockin mice normalized all the blood parameters and the spleen size. Furthermore, deletion of Stat5 com-pletely abrogated erythropoietin (Epo)– independent erythroid colony formation evoked by Jak2V617F, a hallmark feature of PV. Re-expression of Stat5 in Stat5-deficient Jak2V617F knockin mice com-pletely rescued the defects in transforma-tion of hematopoietic progenitors and the PV phenotype. Together, these results indicate a critical function for Stat5 in the pathogenesis of PV. These findings also provide strong support for the develop-ment of Stat5 inhibitors as targeted thera-pies for the treatment of PV and othe