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Lymphoma

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

Leukemia volume 21, pages 788–796 (2007)Cite this article

A Corrigendum to this article was published on 11 November 2009

Abstract

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.

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Acknowledgements

We thank the Belgian Fonds National de la Recherche Scientifique (FNRS, FRSM and Télévie), the Fonds Medic, the Friends of the Bordet Institute, the Belgian Foundation against Cancer for their support and Pr E Sariban for helping us to perform the calcium experiments in his laboratory. H Akl is a scientific collaborator of the FNRS-Télévie. We also thank B Haibe-Kaimo, Dr A Van den Broeke, R Rouas and L Lagneaux for their precious advices.

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Authors and Affiliations

  1. Laboratory of Experimental Hematology, Bordet Institute, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium

    H Akl, B M Badran, K E Willard-Gallo, A Burny & P Martiat

  2. Department of Oncology, Laboratory of Pediatric Oncology, Hopital des Enfants, Brussels, Belgium

    N E Zein

  3. Department of Microbiology, Institute for Microbiological Research J-M Wiame and Laboratory of Microbiology, Université Libre de Bruxelles, Brussels, Belgium

    F Bex

  4. Department of Medical Oncology, Micro-arrays Unit, Bordet Institute, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium

    C Sotiriou

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Correspondence to P Martiat.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Akl, H., Badran, B., Zein, N. et al. 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. Leukemia 21, 788–796 (2007). https://doi.org/10.1038/sj.leu.2404585

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