Jak kinase activity is required for lymphoma invasion and metastasis

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.