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

• Published in: Leukemia Vol. 23; no. 9; pp. 1557 - 1563
• Main Authors: Renouf, B, Hollville, É, Pujals, A, Tétaud, C, Garibal, J, Wiels, J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2009; Nature Publishing Group
• Subjects: Antagonists (Biochemistry); Antigens; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Biopsy; Burkitt Lymphoma - drug therapy; Burkitt Lymphoma - pathology; Burkitt Lymphoma - virology; Burkitt's lymphoma; Cancer Research; Cancer therapies; Cell Cycle - drug effects; Cell Line, Tumor; Cells; Critical Care Medicine; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - physiology; Drug Resistance, Neoplasm; Drug therapy; Epstein-Barr virus; Etoposide; Etoposide - pharmacology; Genes; Genetic aspects; Health aspects; Hematologic and hematopoietic diseases; Hematology; Herpesvirus 4, Human - isolation & purification; Humans; Imidazoles - pharmacology; Inactivation; Infections; Infectious diseases; Intensive; Internal Medicine; Latency; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma; MDM2 protein; Medical sciences; Medicine; Medicine & Public Health; Melphalan; Mutation; Oncology; original-article; p53 Protein; Patients; Piperazines - pharmacology; Poly(ADP-ribose) Polymerases - metabolism; Proteins; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Risk factors; siRNA; Tumor Suppressor Protein p53 - physiology; Tumors; Viral diseases; Viral infections; Viruses; France; EBV; nutlin-3; p21; p53; Burkitt's lymphoma; Nutlin; E; Epstein Barr virus; mdm2 Gene; TP53 Gene; Lymphoproliferative syndrome; Antagonist; Protooncogene; Tumor suppressor gene; Gammaherpesvirinae; Hematology; Herpesviridae; Burkitt lymphoma; B cell neoplasm; Malignant hemopathy; Non Hodgkin lymphoma; Infection; Virus; Viral disease; C-Onc gene; Cancer; Apoptosis
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2009.92

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. p21 WAF1 which is overexpressed in the latter, is involved in this protective effect, as siRNA-mediated inhibition of p21 WAF1 restores sensitivity to etoposide. Nutlin-3 protects latency III BL cells by inducing a p21 WAF1 -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.