Endothelial Cells Harbouring the JAK2V617F Mutation Display Pro-Adherent and Pro-Thrombotic Features

Anna Guadall; Elodie Lesteven; Gil Letort; Sarah Awan Toor; Marc Delord; Doriane Pognant; Mégane Brusson; Emmanuelle Verger; Nabih Maslah; Stéphane Giraudier; Jerome Larghero; Valerie Vanneaux; Christine Chomienne; Wassim El Nemer; Bruno Cassinat; Jean-Jacques Kiladjian

doi:10.1055/s-0038-1667015

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2018; 118(09): 1586-1599
DOI: 10.1055/s-0038-1667015

Endothelium and Angiogenesis

Georg Thieme Verlag KG Stuttgart · New York

Endothelial Cells Harbouring the JAK2^V617F Mutation Display Pro-Adherent and Pro-Thrombotic Features

Anna Guadall^*

¹INSERM, UMRS_1131, Institut Universitaire d'Hématologie, Université Paris-Diderot, Hopital Saint-Louis, Paris, France

,

Elodie Lesteven^*

¹INSERM, UMRS_1131, Institut Universitaire d'Hématologie, Université Paris-Diderot, Hopital Saint-Louis, Paris, France

,

Gil Letort

¹INSERM, UMRS_1131, Institut Universitaire d'Hématologie, Université Paris-Diderot, Hopital Saint-Louis, Paris, France

,

Sarah Awan Toor

¹INSERM, UMRS_1131, Institut Universitaire d'Hématologie, Université Paris-Diderot, Hopital Saint-Louis, Paris, France

,

Marc Delord

²Bioinformatique, Institut Universitaire d'Hématologie, Université Paris-Diderot, Hopital Saint-Louis, Paris, France

,

Doriane Pognant

¹INSERM, UMRS_1131, Institut Universitaire d'Hématologie, Université Paris-Diderot, Hopital Saint-Louis, Paris, France

,

Mégane Brusson

³INSERM, INTS, Unité Biologie Intégrée du Globule Rouge, Paris, France

,

Emmanuelle Verger

¹INSERM, UMRS_1131, Institut Universitaire d'Hématologie, Université Paris-Diderot, Hopital Saint-Louis, Paris, France

⁴APHP, Laboratoire de Biologie Cellulaire, Hopital Saint-Louis, Paris, France

,

Nabih Maslah

¹INSERM, UMRS_1131, Institut Universitaire d'Hématologie, Université Paris-Diderot, Hopital Saint-Louis, Paris, France

⁴APHP, Laboratoire de Biologie Cellulaire, Hopital Saint-Louis, Paris, France

,

Stéphane Giraudier

¹INSERM, UMRS_1131, Institut Universitaire d'Hématologie, Université Paris-Diderot, Hopital Saint-Louis, Paris, France

⁴APHP, Laboratoire de Biologie Cellulaire, Hopital Saint-Louis, Paris, France

⁵Universite Paris Diderot, Paris, France

,

Jerome Larghero

⁶APHP, Laboratoire de Therapie Cellulaire, Hopital Saint-Louis, Paris, France

,

Valerie Vanneaux

⁶APHP, Laboratoire de Therapie Cellulaire, Hopital Saint-Louis, Paris, France

,

Christine Chomienne

¹INSERM, UMRS_1131, Institut Universitaire d'Hématologie, Université Paris-Diderot, Hopital Saint-Louis, Paris, France

⁴APHP, Laboratoire de Biologie Cellulaire, Hopital Saint-Louis, Paris, France

⁵Universite Paris Diderot, Paris, France

,

Wassim El Nemer

³INSERM, INTS, Unité Biologie Intégrée du Globule Rouge, Paris, France

,

Bruno Cassinat

¹INSERM, UMRS_1131, Institut Universitaire d'Hématologie, Université Paris-Diderot, Hopital Saint-Louis, Paris, France

⁴APHP, Laboratoire de Biologie Cellulaire, Hopital Saint-Louis, Paris, France

,

Jean-Jacques Kiladjian^**

¹INSERM, UMRS_1131, Institut Universitaire d'Hématologie, Université Paris-Diderot, Hopital Saint-Louis, Paris, France

⁵Universite Paris Diderot, Paris, France

⁷APHP, Centre d'Investigations Cliniques, Hopital Saint-Louis, Paris, France

› Institutsangaben

Abstract

Thromboembolic events are the main cause of mortality in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) but their underlying mechanisms are largely unrecognized. The Janus kinase 2 (JAK2)^V617F mutation is the most frequent genetic alteration leading to MPN. Usually found in haematopoietic progenitors and stem cells, this mutation has also been described in endothelial cells (ECs) of MPN patients. In this study, we have questioned the impact of the JAK2^V617F mutation on EC phenotype and functions. We developed an induced pluripotent stem cells strategy to compare JAK2 mutant and wild-type ECs. Transcriptomic assays showed that several genes and pathways involved in inflammation, cell adhesion and thrombotic events were over-represented in JAK2^V617F ECs and expression levels of von Willebrand factor and P-selectin (CD62P) proteins were increased. Finally, we found that leucocytes from MPN patients adhere more tightly to JAK2^V617F ECs. Our results show that JAK2^V617F ECs have a pro-inflammatory and pro-thrombotic phenotype and were functionally pro-adherent.

Keywords

BCR-ABL1-negative myeloproliferative neoplasms - JAK2^V617F mutation - thrombosis - endothelial cells - induced pluripotent stem cells

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Referenzen

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