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Protemic analysis of IL-7 induced signalling effectors involved in lymphoma development Duthie, Kim

Abstract

IL-7 is a cytokine that plays a central role in the development, survival and proliferation of T and B cell lymphocytes. Overexpression of IL-7 in mice (Tg IL-7) leads to both increased proliferation of early T and B cell progenitors and T lymphomas. Genetic evidence indicates that known IL-7 receptor (IL-7R)-dependent proteins, including pro-survival protein Bcl-2, may not be solely responsible for the effects of IL- 7. Earlier studies found that known IL-7-induced signaling proteins dock to a specific tyrosine (Y449) residue on the IL-7R. We have previously shown in a IL7Rα⁴⁴⁹F knock-in model that IL-7-induced lymphomas require Y449 phosphorylation and loss of this phosphorylation confers protection from disease. However, the mechanism by which this lymphoma protection occurs remains unclear. Using this genetic model, we aimed to identify novel signaling effectors important for IL-7-mediated lymphocyte development and lymphomagenesis. An 1TRAQ proteomic analysis was performed comparing CD4 CDW double negative T cell progenitors from mice overexpressing IL-7 (Tg IL-7) (lymphoma prone) to Tg IL-7 mice with a mutated IL-7 receptor (Tg IL-7//IL-7Rα⁴⁴⁹F) (lymphoma protected). Several proteins involved in survival/proliferation and apoptosis as well as cytoskeleton regulation were found to be differentially expressed between the two samples. Three proteins of particular interest, Gimap4, Biti and FKBP 51 were validated by immunoblot analysis and are being further characterized regarding their involvement in IL-7 signaling pathways and lymphomagenesis. These proteins have not been previously implicated with IL-7 and as such may represent novel targets for preventing or treating lymphoma development.

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