Arsenic/interferon specifically reverses 2 distinct gene networks critical for the survival of HTLV-1–infected leukemic cells
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 tr...
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| مؤلفون آخرون: | , , , , , , , , , |
| التنسيق: | article |
| منشور في: |
2003
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| الوصول للمادة أونلاين: | http://hdl.handle.net/10725/11083 https://doi.org/10.1182/blood-2002-09-2986 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://www.bloodjournal.org/content/101/11/4576.short |
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| الملخص: | 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. |
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