부산대학교 도서관

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].sub.1] and [[beta].sub.2], may contribute to CMN pathophysiology remained unclear. [[beta].sub.1] ([[alpha].sub.4][[beta].sub.1]; VLA-4) and [[beta].sub.2] ([[alpha].sub.L][[beta].sub.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.sup.+/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].sub.1] and [[beta].sub.2] integrins for their respective ligands. For [[beta].sub.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].sub.2] integrin antibodies suppress pathologic thrombosis as observed in [JAK2.sup.+/VF] mice. In addition, aberrant homing of [JAK2.sup.+/VF] leukocytes to the spleen was inhibited by neutralizing anti-[[beta].sub.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.
Introduction Chronic myeloproliferative neoplasia (CMN) is a malignant hematopoietic disease characterized by excessive proliferation of one or more myeloid cell lineages as erythrocytes, platelets, or leukocytes. CMN comprises several sub-entities, [...]