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Chronic Myeloproliferative Disorders

HLA-G turns off erythropoietin receptor signaling through JAK2 and JAK2 V617F dephosphorylation: clinical relevance in polycythemia vera

Leukemia volume 22, pages 578–584 (2008)Cite this article

Abstract

HLA-G5 is secreted by erythroblasts in all hematopoietic organs, suggesting a role for this protein in erythropoiesis. To examine this, we analyzed whether HLA-G5 affects the proliferation of UT7/EPO and HEL erythroleukemia cells and characterized the mechanism by which HLA-G5 influences erythropoietin receptor (EPOR) signaling. We show that HLA-G5 inhibits the proliferation of UT7/EPO cells, the EPOR signaling of which is similar to that of normal erythroid progenitors. HLA-G5-mediated inhibition was associated with reduced phosphorylation of JAK2 kinase and that of the downstream signaling proteins STAT-5 and STAT-3. Involvement of JAK2 in erythroid cell proliferation has been highlighted by the role of JAK2 V617F mutation in polycythemia vera (PV), a myeloproliferative disorder characterized by erythroid lineage overproduction. We demonstrate that HLA-G5 downregulates EPOR constitutive signaling of JAK2 V617F-expressing HEL cells, leading to inhibition of cell proliferation through G1 cell cycle arrest. Combination of HLA-G5 with JAK inhibitor I further decreases HEL cell growth. Clinical relevance is provided by analysis of PV patients who carry JAK2 V617F mutation, showing that HLA-G5 inhibits the formation of erythropoietin-independent erythroid colonies. Such HLA-G5-mediated inhibition constitutes a new parameter to be considered in the design of future approaches aimed at treating JAK2 V617F-positive myeloproliferative disorders.

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Acknowledgements

We thank Marie-Laurence Menot for establishment of PV diagnosis, Thomas Domet for technical assistance and Abderrahim Naji for statistical analysis. We also thank Dr Bela Papp (Hôpital Saint Louis, Paris, France), Dr Patrick Mayeux (Institut Cochin, Paris, France) and Dr Michael Mac Master (University of California, San Francisco, CA, USA) for the HEL cell line, UT7/EPO cell line and the 4H84 antibody, respectively.

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Authors and Affiliations

  1. Service de Recherches en Hémato-Immunologie, CEA/DSV/I2BM—IUH, Hôpital Saint Louis, Paris, France

    C Menier, C Guillard, E D Carosella & N Rouas-Freiss

  2. Unité de Biologie Cellulaire, AP-HP, Hôpital Saint Louis, Paris, France

    B Cassinat

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  1. C Menier
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  2. C Guillard
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  4. E D Carosella
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Correspondence to C Menier.

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This work was done at the Service de Recherches en Hémato-Immunologie, CEA/DSV/I2BM—IUH, Hôpital Saint Louis, Paris, France.

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Menier, C., Guillard, C., Cassinat, B. et al. HLA-G turns off erythropoietin receptor signaling through JAK2 and JAK2 V617F dephosphorylation: clinical relevance in polycythemia vera. Leukemia 22, 578–584 (2008). https://doi.org/10.1038/sj.leu.2405050

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