Thursday, 09 August 2018 10:55

Impact of hydroxycarbamide and interferon-α on red cell adhesion and membrane protein expression in polycythemia vera

doi:  10.3324/haematol.2017.182303

 

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 Kiladjian,Wassim El Nemer1,2,3

 

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
7Centre d’Investigations Cliniques, Hôpital Saint-Louis, Université Paris Diderot, Paris, France

 

Abstract

Polycythemia vera is a chronic myeloproliferative neoplasm characterized 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 polycythemia vera, erythrocytes had abnormal expression of several proteins including Lu/BCAM adhesion molecule and proteins from the endoplasmic 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 expression, 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 provides 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.