Arsenic-interferon-a–triggered apoptosis in HTLV-I transformed cells is associated with Tax down-regulation and reversal of NF-kB activation

Human T-cell lymphotropic virus type I (HTLV-I)–associated adult T-cell leukemia/ lymphoma (ATL) is a malignancy of mature activated T cells resistant to conventional chemotherapy. The viral transactivator protein Tax plays a critical role in HTLV-I– induced transformation and apoptosis resistance by inducing IkB-a degradation, resulting in the activation of the NF-kBpathway. In these HTLV-I–transformed cells, arsenic trioxide (As) and interferon (IFN)-a synergize to induce cell cycle arrest and apoptosis. We demonstrate that cell death induction is only partly dependent upon caspase activation and is not associated with modulation of bcl-2, bax, or p53 expression. However, combinedAs and IFN induce the degradation of Tax, associated with an up-regulation of IkB-a resulting in a sharp decrease in RelA DNA binding nuclear factor (NF)-kB complexes because of the cytoplasmic retention of RelA. Taken the role of Tax in HTLV-I–induced transformation, its down-regulation probably accounts for cell death induction through inactivation of the NF-kB pathway. Such specific targeting of the viral oncoprotein by As-IFN treatment, reminiscent of As targeting of promyelocytic leukemia/retinoic acid receptor-a in acute promyelocytic leukemia, provides strong rational for combinedAs-IFN therapy in ATL patients. (Blood. 2000;96:2849-2855)