Trinquand, Ameliedos Santos, Nuno R.Quang, Christine TranRocchetti, FrancescaZaniboni, BenedettaBelhocine, Mohamedde Jesus, Cindy Da CostaLhermitte, LudovicTesio, MelaniaDussiot, MichaelCosset, Francois-LoicVerhoeyen, ElsPflumio, FrancoiseIfrah, NorbertDombret, HerveSpicuglia, SalvatoreChatenoud, LucienneGross, David-AlexandreHermine, OlivierMacintyre, ElizabethGhysdael, JacquesAsnafi, Vahid2017-04-072017-04-072016-092159-8274http://hdl.handle.net/10400.1/9312Cancer onset and progression involves the accumulation of multiple oncogenic hits, which are thought to dominate or bypass the physiologic regulatory mechanisms in tissue development and homeostasis. We demonstrate in T-cell acute lymphoblastic leukemia (T-ALL) that, irrespective of the complex oncogenic abnormalities underlying tumor progression, experimentally induced, persistent T-cell receptor (TCR) signaling has antileukemic properties and enforces a molecular program resembling thymic negative selection, a major developmental event in normal T-cell development. Using mouse models of T-ALL, we show that induction of TCR signaling by high-affinity self-peptide/MHC or treatment with monoclonal antibodies to the CD3 epsilon chain (anti-CD3) causes massive leukemic cell death. Importantly, anti-CD3 treatment hampered leukemogenesis in mice transplanted with either mouse-or patient-derived T-ALLs. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of patients with TCR-expressing T-ALL and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells.SIGNIFICANCE: T-ALLs are aggressive malignant lymphoid proliferations of T-cell precursors characterized by high relapse rates and poor prognosis, calling for the search for novel therapeutic options. Here, we report that the lineage-specific TCR/CD3 developmental checkpoint controlling cell death in normal T-cell progenitors remains switchable to induce massive tumor cell apoptosis in T-ALL and is amenable to preclinical therapeutic intervention. (C) 2016 AACR.engjournal article10.1158/2159-8290.CD-15-0675