Page 78 - Haematologica June

980
M. Brusson et al.
tissues, one would expect that Lu/BCAM and CD147 would be also over-expressed in cell types other than RBCs, such as endothelial and epithelial cells. This is sup- ported by our study showing that HC increases the endogenous expression of Lu/BCAM in endothelial cells ex vivo.32 Consequently, overexpression of Lu/BCAM and CD147 in HC-treated patients might possibly have a neg- ative impact both in the vascular territory by promoting abnormal cellular interactions, and in the higher incidence of skin cancer reported in HC-treated PV patients.57
Although HC and IFN inhibit the proliferation of pro- genitor cells, nothing was known about their impact on PV RBCs once they exit the bone marrow. Our study is the first to address the effects of these molecules on PV RBCs, and to show that HC and IFN have a different impact on RBC protein expression and adhesive function. Leukocytosis and high hematocrit are two parameters involved in thrombotic events in MPN patients, and are both decreased during HC treatment.10 A PV Study Group non-randomized trial showed that HC was associated with a lower incidence of early thrombosis compared to a historical cohort treated with phlebotomy alone (6.6% vs. 14% at 2 years).58 Nevertheless, thrombosis is not totally abrogated in HC-treated patients. Patients treated with IFN also encounter less thrombotic events,59 but whether this happens more or less than those treated with HC is still unknown because there had been no clinical trials comparing the effects of both drugs in the same cohort of MPN patients. Such trials are currently ongoing and might show differences between HC and IFN regarding circula- tory complications.
Altogether, our study shows that HC and IFN each have a different impact on RBCs and reveals unexpected
adverse effects of HC on RBC physiology in PV. Our find- ings show that HC deregulates the expression of several proteins at the red cell membrane providing new insights into the effects of this molecule on gene regulation and protein recycling or maturation during erythroid differen- tiation. Furthermore, our study shows that HC increases the expression of two ubiquitously expressed proteins that are linked to progression of solid tumors. Investigating such overexpression in tissues other than blood cells will be of interest in MPNs.
Acknowledgments
We thank Ms. Dominique Gien, Sirandou Tounkara and Eliane Véra at the Centre National de Référence pour les Groupes Sanguins for the management of blood samples, Emilie- Fleur Gautier and Morgane Le Gall for assistance in proteomics data analyses, and the France Intergroupe Syndromes Myéloprolifératifs (FIM) for helpful discussions.
Funding
The research leading to these results has received funding from the Institut National de la Santé et de la Recherche Médicale (Inserm), the Institut National de la Transfusion Sanguine, the European Union’s Horizon 2020 research and innovation pro- gram through the RELEVANCE project under the Marie Skłodowska-Curie grant agreement n. 675115, and the Laboratory of Excellence GR-Ex, reference ANR-11-LABX- 0051. GR-Ex is funded by the program “Investissements d’Avenir” of the French National Research Agency, reference ANR-11-IDEX-0005-02. MB and MDG were funded by the Ministère de l’Enseignement Supérieur et de la Recherche (Ecole Doctorale BioSPC). They received a financial support from: Club du Globule Rouge et du Fer and Société Française d’Hématologie.
References
1. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disor- ders. Lancet. 2005;365(9464):1054-1061.
2. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes poly- cythaemia vera. Nature. 2005; 434(7037):1144-1148.
3. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779-1790.
4. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005; 7(4):387-397.
5. Schafer AI. Bleeding and thrombosis in the myeloproliferative disorders. Blood. 1984; 64(1):1-12.
6. Tefferi A, Barbui T. Essential Thrombocythemia and Polycythemia Vera: Focus on Clinical Practice. Mayo Clin Proc. 2015;90(9):1283-1293.
7. Nazha A, Khoury JD, Verstovsek S, Daver N. Second line therapies in polycythemia vera: What is the optimal strategy after hydroxyurea failure? Crit Rev Oncol Hematol. 2016;105:112-117.
8. Gwilt PR, Tracewell WG. Pharmacokinetics and pharmacodynamics
of hydroxyurea. Clin Pharmacokinet. 1998;
34(5):347-358.
9. Yarbro JW. Mechanism of action of
hydroxyurea. Semin Oncol. 1992;19(3
Suppl 9):1-10.
10. Marchioli R, Finazzi G, Specchia G, et al.
Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33.
11. Kiladjian JJ, Chevret S, Dosquet C, Chomienne C, Rain JD. Treatment of poly- cythemia vera with hydroxyurea and pipo- broman: final results of a randomized trial initiated in 1980. J Clin Oncol. 2011; 29(29):3907-3913.
12. Kiladjian JJ, Masse A, Cassinat B, et al. Clonal analysis of erythroid progenitors suggests that pegylated interferon alpha-2a treatment targets JAK2V617F clones with- out affecting TET2 mutant cells. Leukemia. 2010;24(8):1519-1523.
13. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces com- plete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065-3072.
14. Kwaan HC, Wang J. Hyperviscosity in polycythemia vera and other red cell abnormalities. Semin Thromb Hemost. 2003;29(5):451-458.
15. Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet. 1978;2(8102):1219-1222.
16. Spivak JL. Polycythemia vera: myths,
mechanisms, and management. Blood.
2002;100(13):4272-4290.
17. De Grandis M, Cambot M, Wautier MP, et
al. JAK2V617F activates Lu/BCAM-mediat- ed red cell adhesion in polycythemia vera through an EpoR-independent Rap1/Akt pathway. Blood. 2013;121(4):658-665.
18. Wautier MP, El Nemer W, Gane P, et al. Increased adhesion to endothelial cells of erythrocytes from patients with poly- cythemia vera is mediated by laminin alpha5 chain and Lu/BCAM. Blood. 2007; 110(3):894-901.
19. Brusson M, Cochet S, Leduc M, et al. Enhanced calreticulin expression in red cells of polycythemia vera patients harbor- ing the JAK2V617F mutation. Haematologica. 2017;102(7):e241-e244.
20. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloprolif- erative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29(6):761-770.
21. Gautier EF, Ducamp S, Leduc M, et al. Comprehensive Proteomic Analysis of Human Erythropoiesis. Cell Rep. 2016; 16(5):1470-1484.
22. Kouroupi E, Kiladjian JJ, Dosquet C, et al. Does increasing the JAK2V617F assay sen- sitivity allow to identify more patients with MPN? Blood Cancer J. 2012;2(5):e70.
23. Bartolucci P, Chaar V, Picot J, et al. Decreased sickle red blood cell adhesion to laminin by hydroxyurea is associated with
haematologica | 2018; 103(6)