Autocrine antiapoptotic stimulation of cultured adult T-cell leukemia cells by overexpression of the chemokine I-309

Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+) T cells c aused by the human T-cell leukemia virus type 1 (HTLV-1). The viral leukemo genesis is critically dependent on its oncoprotein Tax because the protein as well as the virus can immortalize primary human lymphocytes to permanent growth. As a transcriptional transactivator, Tax can stimulate the express ion of distinct cellular genes. Alterations in the expression levels of unk nown growth-relevant genes may contribute to the changed growth properties of Tax-immortalized and leukemic cells. To identify genes that are linked t o Tax transformation and ATL leukemogenesis, this study systematically comp ared the gene expression of cultured cells from patients with acute ATL wit h that of stimulated peripheral blood T lymphocytes. Several overexpressed RNAs that encode signal transduction functions were identified. These inclu de a dual-specific protein phosphatase (PAC1), an interferon-inducible fact or (ISG15), a basic helix-loop-helix transcription factor (DEC-1), and the secreted antiapoptotic, chemokine I-309. The ATL cell culture supernatants contained an antiapoptotic activity that could be specifically inhibited by antibodies directed against I-309. Inhibition of I-309 receptor (CCR8) sig naling by pertussis toxin increased the apoptosis rate of ATL cell cultures in the presence and absence of external apoptotic stimuli. Both the I-309- specific antiapoptotic activity and the proapoptotic effect of inhibitors o f I-309 signaling suggest the existence of an antiapoptotic autocrine loop in ATL cells. Thus, the overexpression of this chemokine may inhibit apopto sis in ATL cells and could substantially contribute to their growth.