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

T 细胞非霍奇金淋巴瘤中 TCR 信号转导异常作为新分类系统的基础。

基本信息

批准号：
18390111
负责人：
WATANABE Toshiki
金额：
$ 10.69万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390111/
关键词：
Cancer Signal transduction T-lymphocytes Virus ウイルス

项目摘要

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.

本课题旨在系统研究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T细胞非霍奇金淋巴瘤的新分类和分子靶向治疗提供新的依据。NF-kB信号通路因其在T细胞生长和其他功能中的普遍意义而受到关注。结果表明，NIK在ATL细胞和霍奇金淋巴瘤中过表达。一种新的NF-kB抑制剂DHMEQ，被证明是有效的克服耐药性时，与传统的细胞毒性药物组合使用。通过对ATL细胞拷贝数异常（等位基因核型分析）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，其中一些基因目前正在研究它们在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，并参与调节细胞运动和迁移。我们的结果表明Ezrin过表达参与ATL细胞迁移的增强。根据ATL细胞表达谱的结果建立了RT-PCR芯片系统，可特异性检测PBMC中的ATL细胞。此外，它表明，从阵列PCR的结果计算的“ATL型得分”显示了将“无症状携带者”分为ATL发展的高风险组和低风险组的可能性。目前正在使用队列样本测试这种可能性。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The CD30 Gene Promoter Microsatellite binds Transcription Factor YinYang 1 (YYl) and shows Genetic Instability in Anaplastic Large Cell Lymphoma

CD30 基因启动子微卫星结合转录因子 YinYang 1 (YYl)，在间变性大细胞淋巴瘤中表现出遗传不稳定性

DOI：
发表时间：
2008
期刊：
Journal of Pathology 214
影响因子：
0
作者：
Franchina M;Woo AJ Dods J;et. al.,
通讯作者：
et. al.,

Induction of apoptosis in Epstein-Barr virus-infected B-lymphocytes by the NF-kB inhibitor DHMEQ

NF-kB 抑制剂 DHMEQ 诱导 Epstein-Barr 病毒感染的 B 淋巴细胞凋亡

DOI：
发表时间：
2008
期刊：
Microbes and Infection (in press)
影响因子：
0
作者：
Miyake A;Dewan MdZ;Ishida T;Watanabe M;Honda M;Sata T;Yamamoto N;Umezawa K;Watanabe T;Horie R.
通讯作者：
Horie R.

IκBα-independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin-Reed-Sternberg cells.

在 Hodgkin-Reed-Sternberg 细胞中 IκBα 独立诱导 NF-κB 及其通过 DHMEQ 的抑制。