Journal Article

JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation

Müller, Andreas J., Oelschlegel, Anja M., Heidel, Florian H., Philipsen, Lars, Saalfeld, Felix C., Isermann, Berend, Edelmann, Bärbel, Kliche, Stefanie, Ghosh, Aniket, Gupta, Nibedita, Schnoeder, Tina M., Müller, Peter, Wolleschak, Denise, Shahzad, Khurrum, Goldschmidt, Jürgen, Weinert, Soenke, Amthauer, Holger, Nimmagadda, Subbaiah Chary, Fischer, Thomas, Braun-Dullaeus, Rüdiger, Mohr, Juliane, Schraven, Burkhart

2018

Overview

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, β1 and β2, may contribute to CMN pathophysiology remained unclear. β1 (α4β1; VLA-4) and β2 (αLβ2; 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 β1 and β2 integrins for their respective ligands. For β1 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-β2 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-β2 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.

• Publisher: American Society for Clinical Investigation
• Subject: Amino Acid Substitution / Animals / CD18 Antigens - genetics / CD18 Antigens - metabolism / Cell Adhesion / Integrin alpha4beta1 - genetics / Integrin alpha4beta1 - metabolism / Integrin beta1 - genetics / Integrin beta1 - metabolism / Intercellular Adhesion Molecule-1 - genetics / Intercellular Adhesion Molecule-1 - metabolism / Janus Kinase 2 - genetics / Janus Kinase 2 - metabolism / Leukocytes - metabolism / Leukocytes - pathology / Lymphocyte Function-Associated Antigen-1 - genetics / Lymphocyte Function-Associated Antigen-1 - metabolism / Mice / Mice, Mutant Strains / Mutation, Missense / rap1 GTP-Binding Proteins - genetics / rap1 GTP-Binding Proteins - metabolism / Spleen - metabolism / Spleen - pathology / Venous Thrombosis - genetics / Venous Thrombosis - metabolism / Venous Thrombosis - pathology