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

J Clin Invest. 2018 Oct 1;128(10):4359-4371. doi: 10.1172/JCI90312. Epub 2018 Jul 19.

Abstract

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.

Keywords: Hematology; Integrins; Thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Spleen / metabolism
  • Spleen / pathology
  • Venous Thrombosis / genetics
  • Venous Thrombosis / metabolism*
  • Venous Thrombosis / pathology
  • rap1 GTP-Binding Proteins / genetics
  • rap1 GTP-Binding Proteins / metabolism

Substances

  • CD18 Antigens
  • Icam1 protein, mouse
  • Integrin alpha4beta1
  • Integrin beta1
  • Lymphocyte Function-Associated Antigen-1
  • Intercellular Adhesion Molecule-1
  • Jak2 protein, mouse
  • Janus Kinase 2
  • Rap1 protein, mouse
  • rap1 GTP-Binding Proteins

Grant support

to TF and FHH