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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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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DOI: https://doi.org/10.1038/leu.2009.92
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