Arsenic/interferon specifically reverses 2 distinct gene networks critical for the survival of HTLV-1-infected leukemic cells

Abstract

Adult T-cell leukemia (ATL) is a severe chemotherapy-resistant malignancy associated with prolonged infection by the human T cell-lymphotropic virus 1 (HTLV-1) retrovirus. Although the Tax viral transactivator is clearly an oncogene, the role of its continuous expression in the maintenance of the transformed phenotype is controversial. Because arsenic trioxide (As) and interferon α (IFN) synergize to induce cell cycle arrest and apoptosis of ATL cells both ex vivo and in vitro, we investigated the effects of As alone and As/IFN combination on gene networks in HTLV-1-infected leukemic cells. The As/IFN combination reduced Tax expression and, accordingly, reversed the Tax-induced constitutive nuclear factor κB (NF-κB) activation. Using DNA microarray analyses, we demonstrated that As rapidly and selectively blocks the transcription of NF-κB-dependent genes in HTLV-1-infected cells only. Reversal of NF-κB activation by As alone resulted from dramatic stabilization of IκB-α and IκB-ε, independently of IκB kinase (IKK) activity modulation or Tax degradation. In contrast, only the As/IFN combination induced late and massive down-regulation of cell cycle-regulated genes, concomitantly with Tax degradation by the proteasome and cell death induction, indicating the importance of continuous Tax expression for ATL cell survival. These 2 successive events likely account for the potent and specific effects of the As/IFN combination in ATL. © 2003 by The American Society of Hematology.