title: 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 alpha (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 kappaB (NF-kappaB) activation. Using DNA microarray analyses, we demonstrated that As rapidly and selectively blocks the transcription of NF-kappaB-dependent genes in HTLV-1-infected cells only. Reversal of NF-kappaB activation by As alone resulted from dramatic stabilization of IkappaB-alpha and IkappaB-epsilon, independently of IkappaB 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.
authors.affiliation: Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Rihab
authors.initials: R
authors.lastname: Nasr
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Marwan E
authors.initials: ME
authors.lastname: El-Sabban
authors.forename: Bertrand
authors.initials: B
authors.lastname: Arnulf
authors.forename: Pierre
authors.initials: P
authors.lastname: Zalloua
authors.forename: Yves
authors.initials: Y
authors.lastname: Lepelletier
authors.forename: Françoise
authors.initials: F
authors.lastname: Bex
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Louis
authors.initials: L
authors.lastname: Staudt
authors.forename: Hugues
authors.initials: H
authors.lastname: de Thé
authors.forename: Ali
authors.initials: A
authors.lastname: Bazarbachi
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002470:Cell Survival / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000378:metabolism; D020869:Gene Expression Profiling; D016356:Gene Products, tax / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D001152:Arsenicals; D016356:Gene Products, tax; D016898:Interferon-alpha; D016328:NF-kappa B; D010087:Oxides; D003546:Cysteine Endopeptidases; D000077237:Arsenic Trioxide