Loss of Pleckstrin-2 reverts vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms

V617F driver mutation of JAK2 is the leading cause of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs). One of the leading causes of mortality and morbidity in MPNs is thrombosis. The pathogenesis of thrombosis in these diseases is unclear. Here we show that Pleckstrin-2 (Plek2), a novel downstream target of the JAK2-STAT5 pathway in myeloid cells, is significantly upregulated in JAK2V617F positive MPN mouse model and patients with MPNs. Loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes including erythrocytosis, neutrophilia, thrombocytosis, and splenomegaly, thereby reverting the widespread vascular occlusions and lethality of JAK2V617F knockin mice. We further demonstrated that the reduced red cell mass is the main contributing factor of the reversion of vascular occlusions. Our study identifies Plek2 as a novel effector of JAK2-STAT5 pathway and a key factor in the pathogenesis of JAK2V617F-induced MPNs.