Browsing by Author "Cosset, F. L."
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- Triggering the TCR developmental checkpoin activates a therapeutically targetable tumor suppressive pathway in T-cell leukemiaPublication . Trinquand, A.; Rodrigues Dos Santos, Nuno; Tran Quang, C.; Belhocine, M.; Jesus, C. da Costa de; Lhermitte, L.; Tesio, M.; Dussiot, M.; Cosset, F. L.; Verhoeyen, E.; Pflumio, F.; Ifrah, N.; Dombret, H.; Spicuglia, S.; Chatenoud, L.; Gross, David-Alexandre; Hermine, Olivier; Macintyre, E.; Ghysdael, Jacques; Asnafi, V.Cancer 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.