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• W2096642590 abstract "Abstract Peripheral T-cell lymphomas (PTCL) constitute a major treatment problem with high mortality rates due to the minimal effectiveness of conventional chemotherapy. Recent findings identified ITK-SYK as the first recurrent translocation in 17% of unspecified PTCLs and showed the overexpression of SYK in more than 90% of PTCLs. Here, we show that the expression of ITK-SYK in the bone marrow of BALB/c mice causes a T-cell lymphoproliferative disease in all transplanted mice within 8 weeks after transplantation. The disease was characterized by the infiltration of spleen, lymph nodes, bone marrow, and skin with CD3+CD4+CD8− and CD3+CD4−CD8− ITK-SYK–positive T-cells accompanied by a systemic inflammatory reaction with upregulation of interleukin 5 and INF-γ. ITK-SYK–positive T-cells showed enhanced apoptosis resistance and INF-γ production in vitro. The disease was serially transplantable, inducing clonal T-cell expansion in secondary recipients. The action of ITK-SYK in vivo was dependent on SYK kinase activity and disease development could be inhibited by the treatment of mice with SYK inhibitors. Interestingly, the translocation of ITK-SYK from the membrane to the cytoplasm, using a point mutation in the pleckstrin homology domain (ITK-SYK R29C), did not abolish, but rather, enhanced disease development in transplanted mice. CBL binding was strongly enhanced in membrane-associated ITK-SYK E42K and was causative for delayed disease development. Our results show that ITK-SYK causes a T-cell lymphoproliferative disease in mice, supporting its role in T-cell lymphoma development in humans. Therefore, pharmacologic inhibition of SYK in patients with U-PTCLs carrying the ITK-SYK fusion protein might be an effective treatment strategy. Cancer Res; 70(15); 6193–204. ©2010 AACR." @default.
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• W2096642590 date "2010-07-28" @default.
• W2096642590 modified "2023-10-03" @default.
• W2096642590 title "The ITK-SYK Fusion Oncogene Induces a T-Cell Lymphoproliferative Disease in Mice Mimicking Human Disease" @default.
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• W2096642590 doi "https://doi.org/10.1158/0008-5472.can-08-3719" @default.
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