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-I)-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-C induced transformation and apoptosis resistance by inducing I kappaB-alpha degradation, resulting in the activation of the NF- kappa Bpathway. In these HTLV-I-transformed cells, arsenic trioxide (As) an d interferon (IFN)-alpha synergize to induce cell cycle arrest and apoptosi s. We demonstrate that cell death induction is only partly dependent upon c aspase activation and is not associated with modulation of bcl-2, bar, or p 53 expression. However, combined As and IFN induce the degradation of Tax, associated with an up-regulation of I kappaB-alpha resulting in a sharp dec rease in ReIA DNA binding nuclear factor (NF)-kappaB complexes because of t he cytoplasmic retention of ReIA, Taken the role of Tax in HTLV-I-induced t ransformation, its down-regulation probably accounts for cell death inducti on through inactivation of the NF-kappaB pathway. Such specific targeting o f the viral oncoprotein by As-IFN treatment, reminiscent of As targeting of promyelocytic leukemia/retinoic acid receptor-or in acute promyelocytic le ukemia, provides strong rational for combined As-IFN therapy in ATL patient s. (C) 2000 by The American Society of Hematology.