HLA-G turns off erythropoietin receptor signaling through JAK2 and JAK2 V617F dephosphorylation: clinical relevance in polycythemia vera.
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.
Service de Recherches en Hémato-Immunologie, CEA/DSV/I2BM-IUH, Hôpital Saint Louis, Paris, France. Catherine.Menier@cea.fr
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Menier
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Guillard
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Cassinat
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Carosella
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Rouas-Freiss
D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D003114:Colony-Forming Units Assay; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects / Q000502:physiology*; D004921:Erythropoietin / Q000502:physiology; D016193:G1 Phase / Q000187:drug effects; D006680:HLA Antigens / Q000097:blood / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D008863:Microspheres; D020125:Mutation, Missense; D010766:Phosphorylation / Q000187:drug effects; D017354:Point Mutation; D011087:Polycythemia Vera / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017467:Receptors, Erythropoietin / Q000187:drug effects* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D004921:Erythropoietin; C507924:JAK2 protein, human; D053614:Janus Kinase 2