| First Author | Edelmann B | Year | 2018 |
| Journal | J Clin Invest | Volume | 128 |
| Issue | 10 | Pages | 4359-4371 |
| PubMed ID | 30024857 | Mgi Jnum | J:266380 |
| Mgi Id | MGI:6202807 | Doi | 10.1172/JCI90312 |
| Citation | Edelmann B, et al. (2018) JAK2-V617F promotes venous thrombosis through beta1/beta2 integrin activation. J Clin Invest 128(10):4359-4371 |
| abstractText | 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, beta1 and beta2, may contribute to CMN pathophysiology remained unclear. beta1 (alpha4beta1; VLA-4) and beta2 (alphaLbeta2; 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 beta1 and beta2 integrins for their respective ligands. For beta1 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-beta2 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-beta2 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. |
