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Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia

Amélie Trinquand 1 Nuno R. Santos 2, 3 Christine Tran Quang 3 Francesca Rocchetti 3 Benedetta Zaniboni 3 Mohamed Belhocine 4, 1 Cindy da Costa Jesus 3 Ludovic Lhermitte 1 Melania Tesio 1 Michael Dussiot 5 François-Loïc Cosset 6 Els Verhoeyen 6, 7 Francoise Pflumio 8 Norbert Ifrah 9 Hervé Dombret 10 Salvatore Spicuglia 4 Lucienne Chatenoud 1 David-Alexandre Gross 11 Olivier Hermine 5 Elizabeth Macintyre 1 Jacques Ghysdael 12, 3 Vahid Asnafi 1, 13
Abstract : 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-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.
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https://hal-amu.archives-ouvertes.fr/hal-01460133
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Submitted on : Tuesday, February 7, 2017 - 4:00:32 PM
Last modification on : Wednesday, October 14, 2020 - 3:50:44 AM

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Amélie Trinquand, Nuno R. Santos, Christine Tran Quang, Francesca Rocchetti, Benedetta Zaniboni, et al.. Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia. Cancer Discovery, American Association for Cancer Research, 2016, 6 (9), pp.972-985. ⟨10.1158/2159-8290.CD-15-0675⟩. ⟨hal-01460133⟩

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