MDM2 is an important negative regulator of p53 tumor suppressor. In this study, we sought to investigate the preclinical activity of the MDM2 antagonist, Nutlin-3a, in Philadelphia positive (Ph+) and negative (Ph-) leukemic cell line models, and primary B-acute lymphoblastic leukemia (ALL) patient samples. We demonstrated that Nutlin-3a treatment reduced viability and induced p53-mediated apoptosis in ALL cells with wild-type p53 protein, in a time and dose-dependent manner, resulting in the increased expression of pro-apoptotic proteins and key regulators of cell cycle arrest. The dose-dependent reduction in cell viability was confirmed in primary blast cells from B-ALL patients, including Ph+ ALL resistant patients carrying the T315I BCR-ABL1 mutation. Our findings provide a strong rational for further clinical investigation of Nutlin-3a in Ph+ and Ph- ALL.

Targeting the p53-MDM2 interaction by the small-molecule MDM2 antagonist Nutlin-3a: A new challenged target therapy in adult Philadelphia positive acute lymphoblastic leukemia patients

TRINO, STEFANIA;IACOBUCCI, ILARIA;ERRIQUEZ, DANIELA;FERRARI, ANNA;GHELLI LUSERNA DI RORÀ, ANDREA;PAPAYANNIDIS, CRISTINA;DERENZINI, ENRICO;SIMONETTI, GIORGIA;LONETTI, ANNALISA;VENTURI, CLAUDIA;CATTINA, FEDERICA;OTTAVIANI, EMANUELA;ABBENANTE, MARIACHIARA;RUSSO, DOMENICO;PERINI, GIOVANNI;MARTINELLI, GIOVANNI
2016

Abstract

MDM2 is an important negative regulator of p53 tumor suppressor. In this study, we sought to investigate the preclinical activity of the MDM2 antagonist, Nutlin-3a, in Philadelphia positive (Ph+) and negative (Ph-) leukemic cell line models, and primary B-acute lymphoblastic leukemia (ALL) patient samples. We demonstrated that Nutlin-3a treatment reduced viability and induced p53-mediated apoptosis in ALL cells with wild-type p53 protein, in a time and dose-dependent manner, resulting in the increased expression of pro-apoptotic proteins and key regulators of cell cycle arrest. The dose-dependent reduction in cell viability was confirmed in primary blast cells from B-ALL patients, including Ph+ ALL resistant patients carrying the T315I BCR-ABL1 mutation. Our findings provide a strong rational for further clinical investigation of Nutlin-3a in Ph+ and Ph- ALL.
2016
Trino, Stefania; Iacobucci, Ilaria; Erriquez, Daniela; Laurenzana, Ilaria; De Luca, Luciana; Ferrari, Anna; Ghelli Luserna Di Rorà, Andrea; Papayannidis, Cristina; Derenzini, Enrico; Simonetti, Giorgia; Lonetti, Annalisa; Venturi, Claudia; Cattina, Federica; Ottaviani, Emanuela; Abbenante, Maria Chiara; Russo, Domenico; Perini, Giovanni; Musto, Pellegrino; Martinelli, Giovanni
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/551225
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