Lonetti, A.Antunes, Isabel LoboChiarini, F.Orsini, E.Buontempo, F.Ricci, F.Tazzari, P. L.Pagliaro, P.Melchionda, F.Pession, A.Bertaina, A.Locatelli, F.McCubrey, J. A.Barata, João T.Martelli, A. M.2022-02-082022-02-082013Leukemia (2014) 28, 1196-12060887-6924http://hdl.handle.net/10451/51176© 2014 Macmillan Publishers Limited All rights reservedConstitutively active phosphoinositide 3-kinase (PI3K) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival and drug resistance. These observations lend compelling weight to the application of PI3K inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the pan-PI3K inhibitor NVP-BKM120 (BKM120), an orally bioavailable 2,6-dimorpholino pyrimidine derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. BKM120 treatment resulted in G2/M phase cell cycle arrest and apoptosis, being cytotoxic to a panel of T-ALL cell lines and patient T lymphoblasts, and promoting a dose- and time-dependent dephosphorylation of Akt and S6RP. BKM120 maintained its pro-apoptotic activity against Jurkat cells even when cocultured with MS-5 stromal cells, which mimic the bone marrow microenvironment. Remarkably, BKM120 synergized with chemotherapeutic agents currently used for treating T-ALL patients. Moreover, in vivo administration of BKM120 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth, thus prolonging survival time. Taken together, our findings indicate that BKM120, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment for T-ALLs that have aberrant upregulation of the PI3K signaling pathway.engT-cell acute lymphoblastic leukemiaPI3KApoptosisCell cycleTargeted therapyChemotherapyjournal article10.1038/leu.2013.3691476-5551