Vascular endothelial cell expression of JAK2 V617F is sufficient to promote a pro-thrombotic state due to increased P-selectin expression.

Thrombosis is the main cause of morbidity and mortality in patients with JAK2(V617F) myeloproliferative neoplasms. Recent studies have reported the presence of JAK2(V617F) in endothelial cells of some patients with myeloproliferative neoplasms. We investigated the role of endothelial cells that express JAK2(V617F) in thrombus formation using an in vitro model of human endothelial cells overexpressing JAK2(V617F) and an in vivo model of mice with endothelial-specific JAK2(V617F) expression. Interestingly, these mice displayed a higher propensity for thrombus. When deciphering the mechanisms by which JAK2(V617F)-expressing endothelial cells promote thrombosis, we observed that they have a proadhesive phenotype associated with increased endothelial P-selectin exposure, secondary to degranulation of Weibel-Palade bodies. We demonstrated that P-selectin blockade was sufficient to reduce the increased propensity of thrombosis. Moreover, treatment with hydroxyurea also reduced thrombosis and decreased the pathological interaction between leukocytes and JAK2(V617F)-expressing endothelial cells through direct reduction of endothelial P-selectin expression. Taken together, our data provide evidence that JAK2(V617)F-expressing endothelial cells promote thrombosis through induction of endothelial P-selectin expression, which can be reversed by hydroxyurea. Our findings increase our understanding of thrombosis in patients with myeloproliferative neoplasms, at least those with JAK2(V617F)-positive endothelial cells, and highlight a new role for hydroxyurea. This novel finding provides the proof of concept that an acquired genetic mutation can affect the pro-thrombotic nature of endothelial cells, suggesting that other mutations in endothelial cells could be causal in thrombotic disorders of unknown cause, which account for 50% of recurrent venous thromboses.