Activating JAK1 mutations contribute to multiple-step tumorigenesis by interacting with endogenous cytokine receptor complexes
(2010)
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- (en) JAK1 is a tyrosine kinase from the Janus protein kinase (JAK) family, which includes also JAK2, JAK3 and TYK2. These protein kinases are associated with cytokine receptors to mediate intracellular signaling upon cytokine binding. JAK kinases control activation of downstream signaling molecules such as STAT transcription factors to regulate proliferation, differentiation and cellular growth of target cells. We developed a two-step selection in vitro model of cellular transformation based on the IL-3-dependent pro-B cell line BaF3 that overcame defects in IL-9 receptor signal transduction by spontaneously overexpressing JAK1 during a first step of selection. We identified 18 activating de novo mutations of JAK1 as a second genetic event associated with cytokine-independent proliferation and constitutive activation of the JAK-STAT pathway. In parallel to these observations, in collaboration with Prof. Marco Tartaglia, we identified activating mutations in JAK1 in 20 % of T-cell acute lymphoblastic leukemia (T-ALL) patients and in 3% of B-ALL patients, confirming the relevance of our in vitro model-derived JAK1 mutations for human malignancies. Focusing on the mechanisms by which the JAK1 mutants might promote the development of these leukemias, we found that they need to associate with JAK1-binding cytokine receptors such as the receptors for IL-2 and IL-9, which play an important role in proliferation and differentiation of normal T lymphocytes. When the JAK1 mutants are present, these receptors are constitutively active, even without their ligand. In addition, we observed that JAK1 mutants also associate with the interferon (IFN) receptors. Therefore, tumor cells with mutated JAK1 constitutively express IFN target genes. Moreover, cells with JAK1 mutations are hypersensitive to IFN stimulation. This is particularly relevant for patients because IFN is known to have anti-proliferative activity on tumor cells. We have demonstrated the potential application of this finding by using a mouse model of acute lymphoblastic leukemia. In this model, treatment with IFN resulted in prolonged anti-tumoral protection of the mice that had tumors with JAK1 mutations, as compared to the tumors without such mutations. Based on these observations, we think that IFN- should be considered as a part of the current multi-drug protocol to treat ALL patients positive for JAK1 mutations, and maybe other cancers such as acute myeloid leukemia (AML), where JAK1 mutations occur too.
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Hornakova, T. (2010). Activating JAK1 mutations contribute to multiple-step tumorigenesis by interacting with endogenous cytokine receptor complexes. https://hdl.handle.net/2078.5/130163