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Author Notes:

Correspondence: Dr M Zhou, Division of Hematology/Oncology, Department of Pediatrics, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA 30322, USA. Email: mzhou@emory.edu

Subject:

Research Funding:

This work was supported by grants from the Leukemia and Lymphoma Society (6249-05 and 6033-08), CURE Childhood Cancer and Hope Street Kids (HSK).

Keywords:

  • MDM2
  • p53
  • nutlin-3

MDM2 antagonist nutlin-3 is a potent inducer of apoptosis in pediatric acute lymphoblastic leukemia cells with wild-type p53 and overexpression of MDM2

Tools:

Journal Title:

Leukemia

Volume:

Volume 22, Number 4

Publisher:

, Pages 730-739

Type of Work:

Article | Post-print: After Peer Review

Abstract:

In pediatric acute lymphoblastic leukemia (ALL), overexpression of murine double minute 2 (MDM2) protein 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 this 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 phenotype. 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 proapoptotic proteins and by p53-induced repression of the anti-apoptotic protein survivin. As 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.

Copyright information:

© 2008 Nature Publishing Group All rights reserved

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