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Cited by 138Myeloproliferative Neoplasms: Diagnosis and TreatmentPlatelet Disorders and TreatmentsCell Adhesion Molecules Research

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

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Edelmann, Bärbel, Gupta, Nibedita, Schnoeder, Tina M., Oelschlegel, Anja M., Shahzad, Khurrum, Goldschmidt, Jürgen, Philipsen, Lars, Weinert, Soenke +14 more·2018·Journal of Clinical Investigation
DOI 10.1172/jci90312PMC PMC6159978
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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.

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  • The most prevalent JAK2 missense variant associated with CH and myeloproliferative disorders (V617F) is thought to promote venous thrombosis by activating the integrin β2 pathway.

    “The most prevalent JAK2 missense variant associated with CH and myeloproliferative disorders (V617F) is thought to promote venous thrombosis by activating this pathway46.”

    From Rare variant associations with plasma protein levels in the UK Biobank (2023) · cites this paper as [46]

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Cited by

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Authors
Edelmann, B., Gupta, N., Schnoeder, T. M., Oelschlegel, A. M., Shahzad, K., Goldschmidt, J., Philipsen, L., Weinert, S., Ghosh, A., Saalfeld, F. C., Nimmagadda, S. C., Müller, P., Braun-Dullaeus, R., Mohr, J., Wolleschak, D., Kliche, S., Amthauer, H., Heidel, F. H., Schraven, B., Isermann, B., Müller, A. J., & Fischer, T.
Affiliations
  • Otto-von-Guericke-Universität Magdeburg (DE)
  • Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
  • Leibniz Institute for Neurobiology (DE)
  • Klinikum Magdeburg (DE)
  • Helmholtz Centre for Infection Research (DE)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2018-07-19
Volume
128
Issue
10
Pages
4359-4371
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci90312
PMC
PMC6159978
OpenAlex
W2884701867
Cited by
138
References
0
Citations by year
2026: 8 · 2025: 15 · 2024: 26 · 2023: 10 · 2022: 14 · 2021: 22 · 2020: 22 · 2019: 16 · 2018: 5
FWCI
9.21
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion)
  • HZI (Helmholtz Centre for Infection Research) (submittedVersion, cc-by-nc-sa)
Funders
  • German Ministry of Education and Research (e.bio JAK-Sys)
  • Else-Kröner-Fresenius Foundation (Else-Kröner Forschungskolleg Magdeburg)
  • German Research Council (SFB854)
  • Jose-Carreras-Foundation (DJCLS F)
  • Thuringian Ministry for Research (RegenerAging - FSU-I-03/14)
Topics
  • Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Keywords
JAK2 V617F mutation, venous thrombosis, beta1 integrin, beta2 integrins, VLA-4, LFA-1, integrin activation, Rap1, leukocyte adhesion, VCAM-1, ICAM-1, leukocyte homing, spleen
MeSH terms
Animals, Cell Adhesion, Leukocytes, Mice, Mutant Strains, Spleen, Lymphocyte Function-Associated Antigen-1, Intercellular Adhesion Molecule-1, CD18 Antigens, Integrin beta1, Amino Acid Substitution, Mutation, Missense, Venous Thrombosis, rap1 GTP-Binding Proteins, Integrin alpha4beta1, Mice, Janus Kinase 2

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