Arsenic-interferon-alpha-triggered apoptosis in HTLV-I transformed cells is associated with Tax down-regulation and reversal of NF-kappa B activation

Human T-cell lymphotropic virus type I (HTLV-l)-associated adult T-cell leu kemia/ 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 I kappa B-alpha degradation, resulting in the activation of the N F-kappa Bpathway. In these HTLV-I-transformed cells, arsenic trioxide (As) and interferon (IFN)-alpha synergize to induce cell cycle arrest and apopto sis, We demonstrate that cell death induction is only partly dependent upon caspase activation and is not associated with modulation of bcl-2, bar, or p53 expression. However, combined As and IFN induce the degradation of Tax , associated with an up-regulation of I kappa B-alpha resulting in a sharp decrease in RelA DNA binding nuclear factor (NF)-kappa B complexes because of the cytoplasmic retention of RelA. Taken the role of Tax in HTLV-I-induc ed transformation, its down-regulation probably accounts for cell death ind uction through inactivation of the NF-kappa B pathway. Such specific target ing of the viral oncoprotein by As-IFN treatment, reminiscent of As targeti ng of promyelocytic leukemia/retinoic acid receptor-or in acute promyelocyt ic leukemia, provides strong rational for combined As-IFN therapy in AIL pa tients. (Blood, 2000;96:2849-2855) (C) 2000 by The American Society of Hema tology.