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Resistance to fludarabine-induced apoptosis in Epstein-Barr virus infected B cells

Oncogene volume 21, pages 4473–4480 (2002)Cite this article

Abstract

The Epstein-Barr virus (EBV) transforms B cells in part by inhibiting the cellular apoptotic programme. This is also observed when Burkitt lymphoma cell lines are infected with EBV. Induction of apoptosis is one of the mechanisms by which fludarabine inhibits the growth of cells with low proliferative capacity. This compound can also inhibit several other mechanisms in the cell, including inhibition of the synthesis of factors such as STAT1. To analyse the relationship between EBV status, fludarabine-induced apoptosis, and transcription factors we studied the EBV-negative Burkitt lymphoma cell line BL2, its EBV-infected counterpart BL2.B95.8 and the EBV-transformed cell line PRI. The BL2 cell line was found to be very sensitive to fludarabine. The BL2.B95.8 and PRI cells were both resistant but the latter to a lesser extent. In the PRI cells fludarabine activated p53, but not in the BL2.B95.8 cells in which the p53 pathway is inactivated. We observed that this inactivation results in part from the lack of expression of the MDM2 inhibitor p14ARF. Conversely, there was a substantial constitutive activation of STAT1, and not of the other STATs, in the BL2.B95.8 cells and a modest one in the PRI cells. Furthermore, expression of STAT1 was significantly reduced by fludarabine treatment in the PRI cells, but not in the BL2.BL95.8 cells. Finally, the expression of p21WAF1/CIP1 was detected only in the BL2.B95.8 and PRI cells. This protein, known to play a role in cell survival, may therefore be involved in the resistance of the BL2.B95.8 cells to fludarabine.

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Acknowledgements

The Association de Recherche sur le Cancer (ARC) (grant 5861) and the Ligue contre le Cancer (Comité départemental 93) supported this work.

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Authors and Affiliations

  1. EA 3406 (ATHSCO), Université Paris 13 UFR SMBH, Bobigny cedex, France

    Remi Fagard, Houria Mouas, Antoine Martin, Huynh Van Tan, Jean Feuillard & Martine Raphaël

  2. Service de biochimie, Hôpital Avicenne (APHP), 125 rue de Stalingrad, Bobigny cedex, 93009, France

    Remi Fagard & Christine Devillers

  3. Service d'hématologie biologie, Hôpital Avicenne (APHP), 125 rue de Stalingrad, Bobigny cedex, 93009, France

    Houria Mouas, Philippe Bissières, Jean Feuillard & Martine Raphaël

  4. Service d'anatomie pathologie, Hôpital Avicenne (APHP), 125 rue de Stalingrad, Bobigny cedex, 93009, France

    Antoine Martin

  5. ICGM unité INSERM 363., 27 rue du Fg St Jacques, Paris, 75014, France

    Isabelle Dusanter-Fourt

  6. Institut Gustave Roussy Villejuif cedex, France

    Gilbert Lenoir

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  1. Remi Fagard
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Correspondence to Remi Fagard.

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Fagard, R., Mouas, H., Dusanter-Fourt, I. et al. Resistance to fludarabine-induced apoptosis in Epstein-Barr virus infected B cells. Oncogene 21, 4473–4480 (2002). https://doi.org/10.1038/sj.onc.1205554

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