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

本项目旨在系统表征t细胞非霍奇金淋巴瘤中t细胞受体（TCR）信号转导通路的异常，为分子靶向治疗的新分类和新模式提供新的基础。NF-kB通路由于其在t细胞生长和其他功能中的普遍意义而首先受到关注。结果表明，NIK在ATL细胞和霍奇金淋巴瘤中均有过表达。一种新的NF-kB抑制剂DHMEQ与常规细胞毒药物联合使用时，可有效克服耐药。对ATL细胞拷贝数异常（等位基因-核型）的综合分析揭示了ATL细胞的特征性染色体畸变，为基于基因型的ATL新分类提供了依据。结果还揭示了100多个潜在的靶基因，其中一些正在研究它们在ATL细胞转化和增殖中的作用。ATL细胞的表达谱显示Ezrin过表达，Ezrin连接膜结构和细胞骨架，参与细胞运动和迁移的调节。结果表明，Ezrin过表达参与了ATL细胞迁移的增强。以ATL细胞表达谱分析结果为基础，建立RT-PCR阵列系统，特异性检测PBMC中的ATL细胞。此外，从阵列PCR结果计算的“ATL型评分”显示了将“无症状携带者”划分为ATL发展高、低风险组的可能性。目前正在使用队列样本测试这种可能性。

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.