ITK-SYK Induces T-Cell Lymphoma with Accompanying Inflammatory Disease in Mice.

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The ITK-SYK fusion protein was previously described to be present in 17% of unspecified peripheral T-cell lymphomas. Here we demonstrate that expression of ITK-SYK in the bone marrow of Balb\\c mice causes T-cell lymphomas in mice with a latency of only 3–4 weeks. The disease is characterized by infiltration of the spleen, lymph nodes, bone marrow and the skin with malignant T-cells and progredient destruction of these organs. The mice die about 2 months after the transplantation due to dramatic weight loss caused by infiltration of T-cells into the colon and because of progredient anemia end neutropenia due to progredient infiltration of the bone marrow. The malignant T-cells were characterized as a mixed population of CD3+, CD4+, CD8- T cells and CD3+, CD4-, CD8- T-cells. The malignant disease was accompanied by a generalized inflammatory reaction including upregulation of the inflammatory cytokines IL-5 and INF-γ. Modulation of the membrane binding of ITK-SYK or its binding to Cbl by point mutations in the pleckstrin homology domain of ITK could alter the transforming activity of ITK-SYK. The intact kinase domain was essential for the transformation process and the disease could be reversed by treatment of diseased mice with the Syk-inhibitor Curcumine. Our results demonstrate that the fusion protein ITK-SYK causes T-cell lymphomas in mice and mimics the human disease. Therefore pharmacological inhibition of Syk in patients with U-PTCL carrying the ITK-SYK fusion protein might be a new and effective treatment strategy.