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

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(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).