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Myeloproliferative Neoplasms
Impact of hydroxycarbamide and interferon-α on red cell adhesion and membrane protein expression in polycythemia vera
Mégane Brusson,1,2,3* Maria De Grandis,1,2,3*† Sylvie Cochet,1,2,3
Sylvain Bigot,1,2,3¶ Mickaël Marin,1,2,3 Marjorie Leduc,4 François Guillonneau,4 Patrick Mayeux,4 Thierry Peyrard,1,2,3 Christine Chomienne,5,6
Caroline Le Van Kim,1,2,3 Bruno Cassinat,6 Jean-Jacques Kiladjian7
and Wassim El Nemer1,2,3
Haematologica 2018 Volume 103(2):972-981
1Biologie Intégrée du Globule Rouge UMR_S1134, Inserm, Université Paris Diderot, Sorbonne Paris Cité, Université de la Réunion, Université des Antilles; 2Institut National de la Transfusion Sanguine, F-75015 Paris; 3Laboratoire d’Excellence GR-Ex, Paris; 4Plateforme de Protéomique de l’Université Paris Descartes (3P5), Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Sorbonne Paris Cité, Laboratoire d’Excellence GR-Ex, Paris; 5Université Sorbonne Paris Cité, Université Paris Diderot, Inserm UMR-S1131, Hôpital Saint Louis, Institut Universitaire d'Hématologie, Laboratoire de Biologie Cellulaire, Paris; 6AP-HP, Hôpital Saint-Louis, Laboratoire de Biologie Cellulaire, Paris and 7Centre d'Investigations Cliniques, Hôpital Saint-Louis, Université Paris Diderot, Paris, France
*MB and MDG contributed equally to this work. †Current address: Etablissement Français du Sang PACA Corse, Biologie des Groupes Sanguins, Aix Marseille Université, CNRS, EFS, ADES, Marseille, France; ¶Current address: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France
ABSTRACT
Polycythemia vera is a chronic myeloproliferative neoplasm charac- terized by the JAK2V617F mutation, elevated blood cell counts and a high risk of thrombosis. Although the red cell lineage is primarily affected by JAK2V617F, the impact of mutated JAK2 on circulating red blood cells is poorly documented. Recently, we showed that in poly- cythemia vera, erythrocytes had abnormal expression of several proteins including Lu/BCAM adhesion molecule and proteins from the endoplas- mic reticulum, mainly calreticulin and calnexin. Here we investigated the effects of hydroxycarbamide and interferon-α treatments on the expression of erythroid membrane proteins in a cohort of 53 patients. Surprisingly, while both drugs tended to normalize calreticulin expres- sion, proteomics analysis showed that hydroxycarbamide deregulated the expression of 53 proteins in red cell ghosts, with overexpression and downregulation of 37 and 16 proteins, respectively. Within over- expressed proteins, hydroxycarbamide was found to enhance the expression of adhesion molecules such as Lu/BCAM and CD147, while interferon-α did not. In addition, we found that hydroxycarbamide increased Lu/BCAM phosphorylation and exacerbated red cell adhesion to its ligand laminin. Our study reveals unexpected adverse effects of hydroxycarbamide on red cell physiology in polycythemia vera and pro- vides new insights into the effects of this molecule on gene regulation and protein recycling or maturation during erythroid differentiation. Furthermore, our study shows deregulation of Lu/BCAM and CD147 that are two ubiquitously expressed proteins linked to progression of solid tumors, paving the way for future studies to address the role of hydroxycarbamide in tissues other than blood cells in myeloproliferative neoplasms.
Introduction
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) charac- terized by clonal expansion of an abnormal hematopoietic stem cell due in most cases to the V617F activating mutation in the tyrosine kinase JAK2.1-4 PV is marked
Correspondence:
wassim.el-nemer@inserm.fr
Received: October 11, 2017. Accepted: March 21, 2018. Pre-published: March 29, 2018.
doi:10.3324/haematol.2017.182303
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