HTLV-I infection of WE17/10 CD4+ cell line leads to progressive alteration of Ca2+ influx that eventually results in loss of CD7 expression and activation of an antiapoptotic pathway involving AKT and BAD which paves the way for malignant transformation
| Autor: | H, Akl, B M, Badran, N El, Zein, N E, Zein, F, Bex, C, Sotiriou, K E, Willard-Gallo, A, Burny, P, Martiat |
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| Rok vydání: | 2007 |
| Předmět: |
CD4-Positive T-Lymphocytes
Gene Expression Regulation Viral Cancer Research Apoptosis Antigens CD7 Biology medicine.disease_cause Cell Line Malignant transformation chemistry.chemical_compound hemic and lymphatic diseases medicine Humans Calcium Signaling Protein kinase B PI3K/AKT/mTOR pathway Regulation of gene expression Reverse Transcriptase Polymerase Chain Reaction Ionomycin Hematology Flow Cytometry HTLV-I Infections Oncogene Protein v-akt Antiapoptotic Agent Cell Transformation Neoplastic Oncology chemistry Immunology Cancer research RNA Phosphorylation bcl-Associated Death Protein Carcinogenesis |
| Zdroj: | Leukemia. 21:788-796 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/sj.leu.2404585 |
| Popis: | Adult T-cell leukemia/lymphoma (ATLL) is a malignancy slowly emerging from human T-cell leukemia virus type 1 (HTLV-I)-infected mature CD4(+) T-cells. To characterize the molecular modifications induced by HTLV-I infection, we compared HTLV-I-infected WE17/10 cells with control cells, using micro-arrays. Many calcium-related genes were progressively downmodulated over a period of 2 years. Infected cells acquired a profound decrease of intracellular calcium levels in response to ionomycin, timely correlated with decreased CD7 expression. Focusing on apoptosis-related genes and their relationship with CD7, we observed an underexpression of most antiapoptotic genes. Western blotting revealed increasing Akt and Bad phosphorylation, timely correlated with CD7 loss. This was shown to be phosphatidylinositol 3-kinase (PI3K)-dependent. Activation of PI3K/Akt induced resistance to the apoptotic effect of interleukin-2 deprivation. We thus propose the following model: HTLV-I infection induces a progressive decrease in CD3 genes expression, which eventually abrogates CD3 expression; loss of CD3 is known to perturb calcium transport. This perturbation correlates with loss of CD7 expression and induction of Akt and Bad phosphorylation via activation of PI3K. The activation of the Akt/Bad pathway generates a progressive resistance to apoptosis, at a time HTLV-I genes expression is silenced, thus avoiding immune surveillance. This could be a major event in the process of the malignant transformation into ATLL. |
| Databáze: | OpenAIRE |
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