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Ferrata Storti Foundation
Myeloproliferative Neoplasms
Vascular endothelial cell expression of JAK2V617F is sufficient to promote a pro-thrombotic state due to increased P-selectin expression
Haematologica 2019 Volume 104(1):70-81
1Univ. Bordeaux, Inserm, UMR1034, Biology of Cardiovascular Diseases, Pessac; 2Univ. Paris Diderot, Inserm, UMRS1148, LVTS, Paris; 3Inserm U1176, Hemostasis Inflammation Thrombosis, Le Kremlin-Bicêtre; 4Univ. Paris XI, Inserm U1170, Gustave Roussy Institute, Villejuif; 5CHU de Bordeaux, Service des Maladies Cardiaques et Vasculaires, Pessac and 6CHU de Bordeaux, Laboratoire d’Hématologie, Pessac, France
Alexandre Guy,1 Virginie Gourdou-Latyszenok,1 Nicolas Le Lay,2
Claire Peghaire,1 Badr Kilani,1 Juliana Vieira Dias,1 Cécile Duplaa,1 Marie-Ange Renault,1 Cécile Denis,3 Jean Luc Villeval,4 Yacine Boulaftali,2 Martine Jandrot-Perrus,2 Thierry Couffinhal1,5 and Chloe James1,6
ABSTRACT
Thrombosis is the main cause of morbidity and mortality in patients with JAK2V617F myeloproliferative neoplasms. Recent studies have
V617F
reported the presence of JAK2 in endothelial cells of some
patients with myeloproliferative neoplasms. We investigated the role of endothelial cells that express JAK2V617F in thrombus formation using an in vitro model of human endothelial cells overexpressing JAK2V617F and an in vivo model of mice with endothelial-specific JAK2V617F expression. Interestingly, these mice displayed a higher propensity for thrombus. When deciphering the mechanisms by which JAK2V617F-expressing endothelial cells promote thrombosis, we observed that they have a pro- adhesive phenotype associated with increased endothelial P-selectin exposure, secondary to degranulation of Weibel-Palade bodies. We demonstrated that P-selectin blockade was sufficient to reduce the increased propensity of thrombosis. Moreover, treatment with hydroxy- urea also reduced thrombosis and decreased the pathological interaction between leukocytes and JAK2V617F-expressing endothelial cells through direct reduction of endothelial P-selectin expression. Taken together, our data provide evidence that JAK2V617F-expressing endothelial cells promote thrombosis through induction of endothelial P-selectin expression, which can be reversed by hydroxyurea. Our findings increase our under- standing of thrombosis in patients with myeloproliferative neoplasms, at least those with JAK2V617F-positive endothelial cells, and highlight a new role for hydroxyurea. This novel finding provides the proof of concept that an acquired genetic mutation can affect the pro-thrombotic nature of endothelial cells, suggesting that other mutations in endothelial cells could be causal in thrombotic disorders of unknown cause, which account for 50% of recurrent venous thromboses.
Introduction
Myeloproliferative neoplasms (MPN) are acquired clonal hematopoietic stem cell disorders, characterized by an increase in one or more myeloid lineages. The Philadelphia chromosome-negative MPN include polycythemia vera with an excess of red blood cells, essential thrombocythemia with an increase of platelets, and pri- mary myelofibrosis.1 More than 90% of patients with polycythemia vera and half of those with essential thrombocythemia and primary myelofibrosis carry a muta- tion in the Janus kinase 2 (JAK2) gene, i.e. JAK2V617F.2-5 JAK2 is a tyrosine kinase that initiates intracellular signaling of various type 1 cytokine receptors, such as erythro- poietin and thrombopoietin receptors.6 The JAK2V617F mutation is responsible for constitutive activation of JAK2 kinase, resulting in subsequent activation of its downstream signaling pathways, ultimately leading to overproduction of myeloid cells.
Correspondence:
chloe.james@inserm.fr.
Received: April 10, 2018. Accepted: August 23, 2018. Pre-published: August 31, 2018.
doi:10.3324/haematol.2018.195321
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/1/70
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