Trinquand, A.Rodrigues Dos Santos, NunoTran Quang, C.Belhocine, M.Jesus, C. da Costa deLhermitte, L.Tesio, M.Dussiot, M.Cosset, F. L.Verhoeyen, E.Pflumio, F.Ifrah, N.Dombret, H.Spicuglia, S.Chatenoud, L.Gross, David-AlexandreHermine, OlivierMacintyre, E.Ghysdael, JacquesAsnafi, V.2017-04-072017-04-072016-070390-6078http://hdl.handle.net/10400.1/9448Cancer 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-affi nity selfpeptide/MHC or treatment with monoclonal antibodies to the CD3ε 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.engjournal article