Abnormalities in TCR signal transduction in T cell non-Hodgkin's lymphoma as a basis for a new classification system.

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This project was aimed at a systematic characterization of abnormalities in T-cell receptor (TCR) signal transduction pathway in T-cell non-Hodgkin's lymphomas, which will provide novel basis for a new classification and new modalities for molecularly targeted therapies. NF-kB pathway was first focused because of its general significance in T-cell growth and other functions. It was revealed that overexpression of NIK in ATL cells as well as Hodgkin's lymphoma. A new NF-kB inhibitor, DHMEQ, was shown to be effective for overcoming the drug resistance when used in combination with conventional cytotoxic drugs. Comprehensive analysis of copy number abnormalities (allelo-karyotyping) of ATL cells revealed characteristic chromosomal aberrations in ATL cells, which may provide basis of new classification of ATL based the genotype. The results also revealed more than 100 potential target genes, some of which are now under investigation as to their roles in transformation and proliferation of ATL cells. Expression profiling of ATL cells demonstrated overexpression of Ezrin, which connect membrane structure and cyto-skeleton, and is involved in regulation of cell motility and migration. Our results showed that Ezrin overexpression is involved in enhanced migration of ATL cells. An RT-PCR array system was established based on the expression profiling results of ATL cells, which can specifically detect ATL cells in PBMC. Furthermore, it was shown that the "ATL-type score" calculated from the results of array PCR showed a possibility to dissect "asymptomatic carriers" into high and low risk groups for ATL development. The possibility is now being tested using cohort samples.