Characterization of genes involved in the multistep leukemogenesis of ATL

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Long latent period and absence of HTLV-1 gene expression in leukemic cells of ATL suggest a multistep leukemogenesis of HTLV-1-infected T cells. To explore molecular mechanisms the leukemogenesis, we characterized gene expresssion profiles in primary ATL cells comparing with those in activated normal T cells using fluorescence differential display (FDD) method. To date, 29 cDNA fragments with dysregulated expression were characterized. Overexpression of PKCbeta II was confirmed by Northern blot and immunoblot analyzes in fresh ATL cells and cell lines derived from ATL clone, as well as HTLV-1 unrelated leukemic cell lines, but not in in Vitro transformed HTLV-1-infected T cell lines or Tax-immortalized cell lines. Constitutive activation of PKCbeta II was demonstrated by immune complex kinase assay in these cells. Some of the signal transducers for protein tyrosine kinases involved in TCR signaling were also found to be aberrantly expressed in ATL.These results suggest that overexpression of PKCbeta II may be involved in transformation of HTLV-1-infected T cells in vivo. A novel receptor-like membrane of about 37kDa was found to be overexpressed in ATL.The gene was conserved among species and was mapped at human chromosome 12q21. Along with these, we found that the 5' regionHTLV-1 provirus integrated in the leukemic cells was defective in 70% of patinets, suggesting that expression of virus genes are dispensable in the late stage of leukemogenesis. Studying the function of CD30, a receptor of TNFR superfamily, that is induced in HTLV-1-infected T cells, we cloned and characterized the rat CD30, and discovered a variant form of CD30 that lacks extracellular and transmembrane domains, is expressed in alveolar macrophages and various leukemia cells including ATL.