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Jak kinase activity is required for lymphoma invasion and metastasis

Oncogene volume 23, pages 6647–6653 (2004)Cite this article

Abstract

Jak tyrosine kinases are activated by interleukins and other growth factors, and promote survival and proliferation of cells in multiple tissues. These kinases are constitutively active in many hematopoietic malignancies and certain carcinomas. We have investigated whether Jak kinases play a role in lymphoma invasion and metastasis. Proliferation and survival of a highly metastatic T-lymphoma was made independent of its constitutively active Jak by expression of active forms of both STAT3 and PI3-kinase. Jak activity was then blocked by the isolated JH2 ‘pseudokinase’ domain of Jak2. In vitro invasion was blocked by the JH2 domain, and the metastatic capacity of the JH2-expressing cells was much reduced. The Jak inhibitor AG490 inhibited invasion as well. Invasion and metastasis of these cells requires activation of the integrin LFA-1 by the CXCR4 chemokine receptor. We show that Jak kinases act downstream of LFA-1. We conclude that Jak kinase activity is essential for lymphoma invasion and metastasis, independent of its role in survival and proliferation, and independent of STAT and PI3K signaling. This indicates that Jak kinases contribute in multiple ways to the induction of malignant behavior.

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Acknowledgements

We thank Henk Starrevelt and Ton Schrauwers for technical assistance in animal experiments; and Anita Pfauth and Frank van Diepen for help with FACS sorting. We are grateful to Dr JE Darnell (Rockefeller University) for providing the constitutively active STAT3 mutant and Dr FM Uckun (Parker Hughes Institute, St Paul) for the Jak3 inhibitor WHI-P131. We thank R van der Kammen and Dr JG Collard for providing the constitutively active p110CAAX PI3K. This research was supported by Grant NKI 2000-2270 from the Dutch Cancer Society.

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  1. Division of Cell Biology, The Netherlands Cancer Institute, 121 Plesmanlaan, Amsterdam, 1066 CX, The Netherlands

    Frank J M Opdam, Marga Kamp, Rosalie de Bruijn & Ed Roos

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  1. Frank J M Opdam
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Correspondence to Ed Roos.

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Opdam, F., Kamp, M., de Bruijn, R. et al. Jak kinase activity is required for lymphoma invasion and metastasis. Oncogene 23, 6647–6653 (2004). https://doi.org/10.1038/sj.onc.1207887

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