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

The Journal of Clinical Investigation
Bärbel EdelmannThomas Fischer

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 a...Continue Reading

References

Apr 3, 1999·British Journal of Pharmacology·J PanésD N Granger
Aug 5, 2000·Free Radical Biology & Medicine·A K Hubbard, R Rothlein
Sep 20, 2002·Proceedings of the National Academy of Sciences of the United States of America·Koji EtoSanford J Shattil
Nov 16, 2002·Genesis : the Journal of Genetics and Development·Pantelis GeorgiadesCristin G Print
Feb 5, 2003·The Journal of Experimental Medicine·Charles G LoJason G Cyster
Jul 23, 2003·Journal of Thrombosis and Haemostasis : JTH·V EvangelistaS S Smyth
Apr 27, 2005·Experimental Hematology·Anna FalangaTiziano Barbui
Apr 29, 2005·The New England Journal of Medicine·Robert KralovicsRadek C Skoda
Jun 21, 2005·Nature Reviews. Immunology·Tatsuo Kinashi
Oct 3, 2006·Nature Biotechnology·Walter SchubertAndreas W M Dress
Dec 6, 2006·Cancer Research·Thomas G P BummMichael W N Deininger
Mar 14, 2007·Blood Cells, Molecules & Diseases·Vittorio RostiUNKNOWN Myeloproliferative Disorders Research Consortium
May 12, 2007·The Journal of Clinical Investigation·Wolfgang BergmeierDenisa D Wagner
May 26, 2007·Seminars in Thrombosis and Hemostasis·Ayalew Tefferi, Michelle Elliott
Aug 25, 2007·Nature Reviews. Immunology·Klaus LeySussan Nourshargh
Sep 28, 2007·Annals of Hematology·Alberto Alvarez-LarránFrancisco Cervantes
Dec 15, 2007·The American Journal of Pathology·Alexander Zarbock, Klaus Ley
Nov 3, 2009·Haematologica·Francisco CervantesAlberto Alvarez-Larrán
Mar 12, 2010·Platelets·Lucia Stefanini, Wolfgang Bergmeier
Sep 17, 2010·The New England Journal of Medicine·Srdan VerstovsekAyalew Tefferi
Feb 2, 2011·Nature Reviews. Drug Discovery·Alfonso Quintás-CardamaSrdan Verstovsek
May 21, 2011·Nature Reviews. Immunology·Nancy HoggFrances Willenbrock
Mar 2, 2012·The New England Journal of Medicine·Claire HarrisonGiovanni Barosi
Mar 6, 2012·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Sonam PrakashAttilio Orazi
Mar 28, 2012·The Journal of Experimental Medicine·Marie-Luise von BrühlSteffen Massberg
Jan 2, 2013·The Journal of Experimental Medicine·Florian H HeidelScott A Armstrong

❮ Previous
Next ❯

Citations

Sep 7, 2018·Circulation Journal : Official Journal of the Japanese Circulation Society·Soichi SanoKenneth Walsh
Dec 21, 2018·Circulation Research·Peter LibbyBenjamin L Ebert
Jul 18, 2019·Physiological Reviews·Michael BachmannBernhard Wehrle-Haller
Sep 19, 2019·Médecine sciences : M/S·Alexandre Guy, Chloé James
Apr 7, 2020·Expert Review of Hematology·Thomas Sau-Yan ChanEric Tse
Jul 10, 2020·Current Oncology Reports·Preetham KumarOhad Oren
Aug 30, 2020·Journal of the American Society of Nephrology : JASN·Sabine BrandtPeter R Mertens
Dec 20, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Yunhong ZhangXia Li
Oct 18, 2019·Genes·Lucie LanikovaJosef T Prchal
Aug 11, 2020·Current Heart Failure Reports·Peter BazeleyW H Wilson Tang
Feb 9, 2020·Journal of Thrombosis and Thrombolysis·Leonard NaymagonJohn Mascarenhas
Aug 5, 2020·Journal of Clinical Medicine·Veronica PapaFrancesco Vieceli Dalla Sega
Sep 14, 2020·Journal of Thrombosis and Haemostasis : JTH·Melissa CastiglioneHuichun Zhan
Jul 28, 2019·Journal of the American College of Cardiology·Peter LibbyBenjamin L Ebert
Sep 21, 2019·Journal of the American College of Cardiology·Peter Libby, Göran K Hansson
Jan 28, 2021·International Journal of Molecular Sciences·Francisca Ferrer-MarínRaúl Teruel-Montoya
Dec 9, 2020·Thrombosis Research·Snjezana JanjetovicMinna Voigtlaender
Feb 12, 2021·Haematologica·Tetsuro YokokawaYasuchika Takeishi
Oct 30, 2020·International Journal of Molecular Sciences·Oleg Kandarakov, Alexander Belyavsky
Feb 16, 2021·Hämostaseologie·Anna FalangaFrancesca Schieppati
Mar 2, 2021·Hematology/oncology Clinics of North America·Karie Chen, Alan H Shih
Apr 23, 2021·Military Medicine·Adam K BrustSean D Birmingham
Apr 21, 2021·Current Hematologic Malignancy Reports·Brandi N Reeves, Joan D Beckman
Jul 16, 2021·Clinical Chemistry·Afaf Osman, Jay L Patel
Jun 25, 2021·Cardiovascular Research·Ying WangKenneth Walsh
Aug 15, 2021·Annals of Hematology·Julian BaumeisterDeniz Gezer
Dec 24, 2021·Hämostaseologie·Carolin A Ehlert, Ingo Hilgendorf

❮ Previous
Next ❯

Methods Mentioned

BETA
nucleotide
GTPases
transgenic
flow cytometry
PCR
Transfection
pull-down
fluorescence microscopy

Software Mentioned

InVivoScope
OsiriX DICOM Viewer
NIH ImageJ
Imaris
Excel
Cytobank

Related Concepts

Related Feeds

Adhesion Molecules in Health and Disease

Cell adhesion molecules are a subset of cell adhesion proteins located on the cell surface involved in binding with other cells or with the extracellular matrix in the process called cell adhesion. In essence, cell adhesion molecules help cells stick to each other and to their surroundings. Cell adhesion is a crucial component in maintaining tissue structure and function. Discover the latest research on adhesion molecule and their role in health and disease here.