Stefania Trino 1 , Ilaria Iacobucci 2 , Daniela Erriquez 3 , Ilaria Laurenzana 1 , Luciana De Luca 1 , Anna Ferrari 2 , Andrea Ghelli Luserna Di Rorà 2 , Cristina Papayannidis 2 , Enrico Derenzini 2 , Giorgia Simonetti 2 , Annalisa Lonetti 4 , Claudia Venturi 2 , Federica Cattina 5 , Emanuela Ottaviani 2 , Maria Chiara Abbenante 2 , Domenico Russo 5 , Giovanni Perini 3 , Pellegrino Musto 6 , Giovanni Martinelli 2
12 February 2016
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.