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Journal of Cancer Research and Clinical Oncology

Erschienen in:

23.02.2017 | Original Article – Cancer Research

Cell autonomous expression of CXCL-10 in JAK2V617F-mutated MPN

verfasst von: Tina M. Schnöder, Judith Eberhardt, Michael Koehler, Holger B. Bierhoff, Sönke Weinert, Akhilesh Datt Pandey, Subbaiah Chary Nimmagadda, Denise Wolleschak, Korinna Jöhrens, Thomas Fischer, Florian H. Heidel

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 5/2017

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Abstract

Purpose

Myeloproliferative neoplasms (MPN) are clonal disorders of hematopoietic stem- and progenitor cells. Mutation of Janus-Kinase 2 (JAK2) is the most frequent genetic event detected in Philadelphia-negative MPN. In advanced phases, the clinical hallmark of the disease is a striking inflammatory syndrome. So far, the cellular and molecular basis of inflammation is not fully understood. We, therefore, sought to investigate the relationship of activating JAK2 mutation and aberrant cytokine expression in MPN.

Methods

Cytokine array was performed to identify Jak2V617F-related cytokine expression and secretion. CXCL10 mRNA expression was analyzed by qPCR in peripheral blood cells. To exclude paracrine/autocrine stimulation as a potential mechanism, we generated Ba/F3-EpoR-JAK2WT or EpoR-JAK2V617F cells lacking CXCL10 receptor. Pharmacologic inhibition of JAK2 kinase was achieved by JAK-Inhibitor treatment. Signaling pathways and downstream effectors were characterized by Western blotting, immunofluorescence microscopy, luciferase reporter assays, qPCR, and chromatin-immunoprecipitation studies.

Results

We identified CXCL10 as the most highly induced cytokine in JAK2-mutated cell lines. In MPN patients, CXCL10 is highly expressed in JAK2V617F but not JAK2WT MPN or healthy donor controls. Moreover, CXCL10 expression correlates with JAK2V617F allelic burden. High CXCL10 correlates with the presence of clinical risk factors but not with clinical symptoms and quality of life. Pharmacologic inhibition of mutated JAK2 kinase inhibits CXCL10 expression. NFκB signaling is activated downstream of JAK2V617F receptor and directly induces CXCL10 expression.

Conclusions

Our data provide first evidence for a link between oncogenic JAK2V617F signaling and cell intrinsic induction of CXCL10 induced by activated NFkB signaling.

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Titel: Cell autonomous expression of CXCL-10 in JAK2V617F-mutated MPN
verfasst von: Tina M. Schnöder
Judith Eberhardt
Michael Koehler
Holger B. Bierhoff
Sönke Weinert
Akhilesh Datt Pandey
Subbaiah Chary Nimmagadda
Denise Wolleschak
Korinna Jöhrens
Thomas Fischer
Florian H. Heidel
Publikationsdatum: 23.02.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 5/2017
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-017-2354-1

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Cell autonomous expression of CXCL-10 in JAK2V617F-mutated MPN