The MDM2 Antagonist Nutlin-3 Is a Potent Inducer of Apoptosis in Pediatric Acute Lymphoblastic Leukemia Cells with Wild-Type p53 and Overexpression of MDM2.

In pediatric acute lymphoblastic leukemia (ALL), overexpression of MDM2 by leukemic cells is typically associated with a wild-type (wt) p53 phenotype and chemoresistance. A recently-developed small-molecule antagonist of MDM2, nutlin-3, inhibits the MDM2-p53 interaction, resulting in induction of p53 activity and apoptosis. In the present study, we evaluated the cytotoxic effect of nutlin-3 on ALL cells with different p53 status and MDM2 expression, using 18 cell lines and 30 primary leukemia samples. We found that both ALL cell lines and primary ALL samples with wt-p53 are sensitive to nutlin-3. No cytotoxic effect of nutlin-3 was detected in ALL cells with either p53-mutant or null phenotypes. In wt-p53 ALL cells, there was a significant positive correlation between MDM2 expression levels and sensitivity to nutlin-3. Nutlin-3-induced cell death was mediated by p53-induced activation of pro-apoptotic proteins and by p53-induced repression of the anti-apoptotic protein survivin. Because p53 function is inhibited by MDM2 in chemoresistant, MDM2-overexpressing ALL cells, potent killing of these cells by nutlin-3 suggests that this agent may be a novel therapeutic for refractory ALL.