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Publication : Oncogenic JAK2<sup>V617F</sup> causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms.

First Author	Prestipino A	Year	2018
Journal	Sci Transl Med	Volume	10
Issue	429	PubMed ID	29467301
Mgi Jnum	J:260048	Mgi Id	MGI:6117601
Doi	10.1126/scitranslmed.aam7729	Citation	Prestipino A, et al. (2018) Oncogenic JAK2(V617F) causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms. Sci Transl Med 10(429)

abstractText

Recent evidence has revealed that oncogenic mutations may confer immune escape. A better understanding of how an oncogenic mutation affects immunosuppressive programmed death ligand 1 (PD-L1) expression may help in developing new therapeutic strategies. We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2(V617F)-mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2(V617F)-mutant cells. PD-L1 expression was higher on primary cells isolated from patients with JAK2(V617F)-myeloproliferative neoplasms (MPNs) compared to healthy individuals and declined upon JAK2 inhibition. JAK2(V617F) mutational burden, pSTAT3, and PD-L1 expression were highest in primary MPN patient-derived monocytes, megakaryocytes, and platelets. PD-1 (programmed death receptor 1) inhibition prolonged survival in human MPN xenograft and primary murine MPN models. This effect was dependent on T cells. Mechanistically, PD-L1 surface expression in JAK2(V617F)-mutant cells affected metabolism and cell cycle progression of T cells. In summary, we report that in MPN, constitutive JAK2/STAT3/STAT5 activation, mainly in monocytes, megakaryocytes, and platelets, caused PD-L1-mediated immune escape by reducing T cell activation, metabolic activity, and cell cycle progression. The susceptibility of JAK2(V617F)-mutant MPN to PD-1 targeting paves the way for immunomodulatory approaches relying on PD-1 inhibition.

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Publication : Oncogenic JAK2<sup>V617F</sup> causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms.

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