Browsing by Author "Trinquand, Amelie"
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- Triggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemiaPublication . Trinquand, Amelie; dos Santos, Nuno R.; Quang, Christine Tran; Rocchetti, Francesca; Zaniboni, Benedetta; Belhocine, Mohamed; de Jesus, Cindy Da Costa; Lhermitte, Ludovic; Tesio, Melania; Dussiot, Michael; Cosset, Francois-Loic; Verhoeyen, Els; Pflumio, Francoise; Ifrah, Norbert; Dombret, Herve; Spicuglia, Salvatore; Chatenoud, Lucienne; Gross, David-Alexandre; Hermine, Olivier; Macintyre, Elizabeth; Ghysdael, Jacques; Asnafi, VahidCancer 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.