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JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation
Bärbel Edelmann1,2, Nibedita Gupta1,2, Tina M Schnoeder1,3,4
1Department of Hematology and Oncology, Medical Center, Otto-von-Guericke University, Magdeburg, Germany.
The Journal of Clinical Investigation
|July 20, 2018
Summary
JAK2-V617F mutation enhances leukocyte adhesion and promotes thrombosis by activating integrins. This study reveals a mechanism linking JAK2 mutation to integrin signaling, impacting cell adhesion and leukocyte trafficking in myeloproliferative neoplasms.
Area of Science:
- Hematology
- Molecular Biology
- Immunology
Background:
- JAK2-V617F mutation is common in chronic myeloproliferative neoplasms (CMN).
- Integrin and adhesion molecule dysfunction is observed in CMN, but the role of β1 and β2 integrin chains is unclear.
- β1 (VLA-4) and β2 (LFA-1) integrins regulate leukocyte adhesion to endothelial cells.
Purpose of the Study:
- To elucidate the mechanism by which β1 and β2 integrins contribute to CMN pathophysiology.
- To investigate the role of JAK2-V617F in regulating integrin activation and leukocyte adhesion.
- To assess the therapeutic potential of targeting integrin activation in JAK2-V617F-driven thrombosis and leukocyte trafficking.
Main Methods:
- Compared granulocyte adhesion in JAK2-V617F knockin mice (JAK2+/VF) to controls.
- Utilized soluble VCAM1 and ICAM1 ligand binding assays to assess integrin affinity.
- Employed venous thrombosis models and neutralizing antibodies against VLA-4 and β2 integrins.
- Investigated the role of Rap1 signaling pathway.
Main Results:
- JAK2+/VF granulocytes showed enhanced adhesion to VCAM1 and ICAM1.
- Increased affinity of β1 and β2 integrins for their ligands was observed, with β1 shifting to a high-affinity conformation.
- JAK2-V617F induced constitutive activation of Rap1, leading to its translocation to the cell membrane.
- Anti-VLA-4 and anti-β2 antibodies suppressed thrombosis in JAK2+/VF mice.
- Anti-β2 antibodies and Rap1 inhibition reduced aberrant splenic leukocyte homing.
Conclusions:
- JAK2-V617F directly promotes integrin activation, leading to enhanced leukocyte adhesion and contributing to pathologic thrombosis.
- Constitutive activation of Rap1 is a key mediator of JAK2-V617F-induced integrin signaling.
- Targeting integrin activation pathways, such as Rap1, may offer therapeutic strategies for myeloproliferative neoplasms.
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