Bay 11-7082 inhibits transcription factor NF-κB and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells

Human T-cell leukemia virus type I (HTLV-I) Is the causative agent of an aggressive form of leukemia designated adult T-cell leukemia (ATL). We have previously demonstrated that all T-cell lines Infected with HTLV-I and primary leukemic cells from ATL patients display constitutively high activity of transcription factor NF-B-K. In this study we showed that Bay 11-7082, an Inhibitor of NF-KB, Induced apoptosis of HTLV-I-infected T-cell lines but only negligible apoptosis of HTLV-I-negative T cells. Bay 11-7082 rapidly and efficiently reduced the DNA binding of NF-KB In HTLV-I-infected T-cell lines and down-regulated the expression of the antiapoptotic gene, Bcl-x(L), regulated by NF-KB, whereas It had little effect on the DNA binding of another transcription factor, AP-1. Although the viral protein Tax Is an activator of NF-KB, Bay 11-7082-induced apoptosis of HTLV-I-infected cells was not associated with reduced expression of Tax. Furthermore, Bay 11-7082-induced apoptosis of primary ATL cells was more prominent than that of normal peripheral blood mononuclear cells, and apoptosis of these cells was also associated with down-regulation of NF-KB activity. Our results Indicate that NF-KB plays a crucial role In the pathogenesis and survival of HTLV-I-infected leukemic cells and that It Is a suitable target for the prevention and treatment of ATL.