Jak2-V617f Promotes Venous Thrombosis Through Beta(1)/Beta(2) Integrin Activation

JAK2-V617F-positive chronic myeloproliferative neoplasia (CMN) commonly displays dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes, and leukocytes. However, the mechanism by which the 2 major leukocyte integrin chains, beta(1) and beta(2), may contribute to CMN pathophysiology remained unclear. beta(1) (alpha(4)beta(1); VLA-4) and beta(2) (alpha(L)beta(2); LFA-1) integrins are essential regulators for attachment of leukocytes to endothelial cells. We here showed enhanced adhesion of granulocytes from mice with JAK2-V617F knockin (JAK2(+/)(VF) mice) to vascular cell adhesion molecule 1- (VCAM1-) and intercellular adhesion molecule 1-coated (ICAM1-coated) surfaces. Soluble VCAM1 and ICAM1 ligand binding assays revealed increased affinity of beta(1) and beta(2) integrins for their respective ligands. For beta(1) integrins, this correlated with a structural change from the low- to the high-affinity conformation induced by JAK2-V617F. JAK2-V617F triggered constitutive activation of the integrin inside-out signaling molecule Rap1, resulting in translocation toward the cell membrane. Employing a venous thrombosis model, we demonstrated that neutralizing anti-VLA-4 and anti-beta(2) integrin antibodies suppress pathologic thrombosis as observed in JAK2(+/)(VF) mice. In addition, aberrant homing of JAK2(+/)(VF) leukocytes to the spleen was inhibited by neutralizing anti-beta(2) antibodies and by pharmacologic inhibition of Rap1. Thus, our findings identified cross-talk between JAK2-V617F and integrin activation promoting pathologic thrombosis and abnormal trafficking of leukocytes to the spleen.