JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation.
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Authors
Edelmann, BärbelGupta, Nibedita
Schnoeder, Tina M
Oelschlegel, Anja M
Shahzad, Khurrum
Goldschmidt, Jürgen
Philipsen, Lars
Weinert, Soenke
Ghosh, Aniket
Saalfeld, Felix C
Nimmagadda, Subbaiah Chary
Müller, Peter
Braun-Dullaeus, Rüdiger
Mohr, Juliane
Wolleschak, Denise
Kliche, Stefanie
Amthauer, Holger
Heidel, Florian H
Schraven, Burkhart
Isermann, Berend
Müller, Andreas J
Fischer, Thomas
Issue Date
2018-10-01
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Show full item recordAbstract
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.Affiliation
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.DOI
10.1172/JCI90312PubMed ID
30024857Type
ArticleISSN
1558-8238ae974a485f413a2113503eed53cd6c53
10.1172/JCI90312
Scopus Count
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