Molecular analysis of aberrant signal transduction of membrane receptors as a basis for diagnosis and treatment of malignant lymphomas

(1)霍奇金淋巴瘤和间变性大细胞淋巴瘤（ALCL）：我们证明NF-kB的组成性激活是由霍奇金/里德-斯特恩伯格（H-RS）细胞上过表达的CD30的“配体非依赖性激活”引起的，并且通过缺乏细胞质区域的显性阴性诱饵CD30的转导抑制CD30信号传导诱导H-RS细胞的凋亡细胞死亡（Horie等人，Oncogene 21,2493,2002）。我们发现TRAF2和TRAF5蛋白的细胞质聚集代表CD30的持续信号传导（Horie et al., Am J Pathol 160,1647,2002）。我们证明位于微卫星附近的AP-1结合序列抵消了微卫星对CD30启动子活性的抑制作用（Watanabe et al., Am J Pathol 163,633,2003）。我们发现p80NPM-ALK通过隔离NPM- alk和野生型NPM复合物中的TRAF蛋白，抑制ALCL细胞中过表达CD30的信号转导（Horie et al., Cancer Cell 5,353,2004）。(2)ATL：我们证明GSK-3b-b-catenin-TCF/LEF通路可能是ATL细胞中组成型激活pkcll的下游靶点。ATL细胞表达谱分析发现，ATL细胞中特异性过表达基因67个，HTLV-1携带者PBMC活化t细胞中特异性过表达基因44个，HTLV-1感染细胞系中特异性过表达基因24个。我们发现HTLV-1前病毒在ATL细胞和有症状携带者外周血感染的t细胞中存在5'-LTR特异性CpG重甲基化，这可能是HTLV-1潜伏感染的一个基础（Koiwa et al., J Virol 76,9389,2002）。

(1)Hodgkin's lymphoma and anaplastic large cell lymphomas (ALCL) : We demonstrated that the constitutive activation of NF-kB results from "ligand-independent activation" of overexpressed CD30 on the Hodgkin/Reed-Sternberg (H-RS)cells, and that inhibition of CD30 signaling by transduction of a dominat negative decoy CD30 that lacks the cytoplasmic region induced apoptotic cell death of H-RS cells (Horie et al., Oncogene 21,2493,2002). We shoed that cytoplasmic aggregation of TRAF2 and TRAF5 proteins represents constant signaling of CD30 (Horie et al., Am J Pathol 160,1647,2002). We demonstrated that the AP-1 binding sequence located near the microsatellite counteracts the suppressive effects of the microsatellite on the CD30 promoter activity (Watanabe et al., Am J Pathol 163,633,2003). We showed that p80NPM-ALK inhibits ligand-independent signal transduction by overexpressed CD30 in ALCL cells though sequestration of TRAF proteins in the complex of NPM-ALK and wild type NPM (Horie et al., Cancer Cell 5,353,2004).(2)ATL :We demonstrated that GSK-3b-b-catenin-TCF/LEF pathway is a possible downstream target of the constitutively activated PKCbll in ATL cells.Expression profile analysis of ATL cells identified 67 genes as specifically overexpressed ones in ATL cells, 44 in activated T-cells of PBMC of HTLV-1 carriers, 24 in HTLV-1 infected cell lines.We revealed 5'-LTR specific CpG heavy methylation of HTLV-1 provirus in ATL cells and infected T-cells in peripheral blood of symptomatic carriers, which may be one base for latent infection of HTLV-1 (Koiwa et al., J Virol 76,9389,2002).