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.
Trino, S., Iacobucci, I., Erriquez, D., Laurenzana, I., De Luca, L., Ferrari, A., et al. (2016). 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. ONCOTARGET, 7(11), 12951-12961 [10.18632/oncotarget.7339].
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
