JAK2-V617F activates β1-integrin-mediated adhesion of granulocytes to vascular cell adhesion molecule 1

Gupta, Nandini; Edelmann, Bärbel; Schnoeder, Tina M.; Saalfeld, Felix C.; Wolleschak, Denise; Kliche, Stefanie; Schraven, Burkhart; Heidel, Florian H.

doi:10.1038/leu.2017.26

Cited by 24 publications

(30 citation statements)

References 16 publications

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“…Having demonstrated that β 1 and β 2 integrin activity is increased in JAK2 +/VF granulocytes, we evaluated inside-out signaling of integrins. Rap1-GTPase was recently identified to be constitutively activated in JAK2-V617F-positive human granulocytes and directly involved in activation of β 1 integrins (15). Analysis of JAK2 +/+ and JAK2 +/VF granulocytes confirmed increased activation of Rap1 in JAK2-V617F-mutated mice ( Figure 3A).…”

Section: Resultsmentioning

confidence: 70%

“…A large body of evidence from T cell studies suggests that activation of Rap1-GTP in control of β 1 integrin function is associated with translocation of the protein to the plasma membrane (38). To investigate whether JAK2-V617F kinase causes membrane relocalization of Rap1, we employed the 32D myeloid progenitor cell model ectopically expressing the erythropoietin receptor (Epo-R) and either JAK-WT or JAK2-V617F mutant (15,39). Previously, we demonstrated that 32D JAK2-V617F cells display a strong increase in static adhesion to immobilized VCAM1 (the ligand for β 1 integrin VLA-4) but not to immobilized BSA (15).…”

Section: Resultsmentioning

confidence: 99%

“…To investigate whether JAK2-V617F kinase causes membrane relocalization of Rap1, we employed the 32D myeloid progenitor cell model ectopically expressing the erythropoietin receptor (Epo-R) and either JAK-WT or JAK2-V617F mutant (15,39). Previously, we demonstrated that 32D JAK2-V617F cells display a strong increase in static adhesion to immobilized VCAM1 (the ligand for β 1 integrin VLA-4) but not to immobilized BSA (15). The presence of the mutated JAK2 compared with the JAK2-WT molecule in 32D cells resulted in increased localization of Rap1 in cytoplasm and translocation toward cortical actin ( Figure 3B and Supplemental Figure 4).…”

Section: Resultsmentioning

confidence: 99%

“…Aberrant single-cell cytokine secretion (11) and elevated α M integrin CD11b expression have been described in circulating granulocytes in PV, ET, and MF patients (12)(13)(14). Recently, our group has demonstrated that JAK2-V617F activates β 1 integrin-mediated adhesion of granulocytes isolated from CMN patients to vascular cell adhesion molecule 1 (VCAM1) (15). VCAM1 is expressed on venous endothelial cells and acts in leukocyte-endothelial cell adhesion (16,17).…”

Section: Introductionmentioning

confidence: 99%

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

Edelmann¹,

Gupta²,

Schnoeder³

et al. 2018

Journal of Clinical Investigation

104

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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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Section: Resultsmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Edelmann¹,

Gupta²,

Schnoeder³

et al. 2018

Journal of Clinical Investigation

104

View full text Add to dashboard Cite

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“…Moreover, GGTI-2147, a geranylgeranyltransferase inhibitor that blocks the posttranslational modifications required for Rap1 activation and translocation to the plasma membrane, inhibited adhesion of JAK2-mutant (but not JAK2-WT) granulocytes to VCAM1. JAK2-mutant ing that granulocytes from JAK2-mutant MPN patients have increased adhesion to VCAM1 (14).…”

Section: Perspectivementioning

confidence: 99%

Neutralize the neutrophils! Neutrophil β1/β2 integrin activation contributes to JAK2-V617F–driven thrombosis

Oh¹

2018

Journal of Clinical Investigation

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Adrenal infarction with latent myelodysplastic/myeloproliferative neoplasm, unclassifiable with JAK2V617F mutation

Yasuda,

Chiba,

Nishitani

et al. 2024

Clinical Case Reports

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Key Clinical MessageHematopoietic neoplasms can cause adrenal infarction. In cases of thrombosis occurring at uncommon sites, it is necessary to consider evaluating for the JAK2V617F mutation, even in the absence of notable abnormalities in blood counts.AbstractAdrenal infarction, a rare ailment, has been sporadically linked to hematopoietic neoplasms. A 46‐year‐old male encountered left adrenal infarction, which coincided with a progressive rise in platelet counts. Subsequent diagnosis revealed myelodysplastic/myeloproliferative neoplasm‐unclassifiable, featuring a JAK2V617F mutation. Simultaneously, the patient manifested multiple arteriovenous thromboses, necessitating treatment with edoxaban, aspirin, and hydroxyurea. Following thrombosis resolution, he was transferred to a transplantation center. This report delves into the thrombogenicity linked to the JAK2V617F mutation, while also examining documented instances of adrenal infarction in myeloid neoplasms. We should consider evaluating for JAK2V617F mutation even in cases of thrombosis at unusual sites, including adrenal infarction, even if there are no considerable abnormalities in blood counts.

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JAK2-V617F activates β1-integrin-mediated adhesion of granulocytes to vascular cell adhesion molecule 1

Cited by 24 publications

References 16 publications

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

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

Neutralize the neutrophils! Neutrophil β1/β2 integrin activation contributes to JAK2-V617F–driven thrombosis

Adrenal infarction with latent myelodysplastic/myeloproliferative neoplasm, unclassifiable with JAK2V617F mutation

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