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Therapy

Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein–Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cells

Leukemia volume 23, pages 1557–1563 (2009)Cite this article

Abstract

p53 inactivation is often observed in Burkitt's lymphoma (BL) cells, because of either mutations in p53 gene or an overexpression of the p53-negative regulator MDM2. Epstein–Barr virus (EBV) is present in virtually 100% of BL cases occurring in endemic areas, but in only 10–20% of sporadic cases. In EBV(−) BL cells, reactivation of p53, induced by reducing MDM2 protein level, led to apoptosis. We show here that nutlin-3, a potent antagonist of MDM2, activates the p53 pathway in all BL cell lines harboring wild-type p53, regardless of EBV status. However, nutlin-3 strongly induced apoptosis in EBV(−) or latency I EBV(+) cells, whereas latency III EBV(+) cells were much more resistant. Prior treatment with sublethal doses of nutlin-3 sensitizes EBV(−) or latency I EBV(+) cells to apoptosis induced by etoposide or melphalan, but protects latency III EBV(+) cells. p21WAF1 which is overexpressed in the latter, is involved in this protective effect, as siRNA-mediated inhibition of p21WAF1 restores sensitivity to etoposide. Nutlin-3 protects latency III BL cells by inducing a p21WAF1-mediated G1 arrest. Most BL patients with wild-type p53 tumors could therefore benefit from treatment with nutlin-3, after a careful determination of the latency pattern of EBV in infected patients.

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Acknowledgements

This work was supported by grants from the Fondation de France 2002004543 (JW); Association pour la recherche sur le Cancer 3454 (JW and EH); Société Française du cancer and Société Française d'Hématologie (BR). We thank Yann Lécluse for expert technical assistance in performing flow cytometry analysis.

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  1. B Renouf

    Present address: 2Current address: INSERM U682, Hôpital de Hautepierre, Strasbourg, France,

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  1. UMR 8126 CNRS, Univ Paris-Sud, Institut Gustave Roussy, Villejuif, France

    B Renouf, É Hollville, A Pujals, C Tétaud, J Garibal & J Wiels

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Renouf, B., Hollville, É., Pujals, A. et al. Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein–Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cells. Leukemia 23, 1557–1563 (2009). https://doi.org/10.1038/leu.2009.92

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