title: Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia.
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 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.
  
  
  
  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. Cancer Discov; 6(9); 972-85. ©2016 AACR.See related commentary by Lemonnier and Mak, p. 946This article is highlighted in the In This Issue feature, p. 932.
authors.affiliation: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Trinquand
authors.affiliation: Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal. Institut Curie, PSL Research University, CNRS UMR 3348, Orsay, France.
authors.forename: Nuno R
authors.initials: NR
authors.lastname: Dos Santos
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR 3348, Orsay, France. Université Paris Sud, Université Paris-Saclay, CNRS UMR 3348, Orsay, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Tran Quang
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR 3348, Orsay, France. Université Paris Sud, Université Paris-Saclay, CNRS UMR 3348, Orsay, France.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rocchetti
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR 3348, Orsay, France. Université Paris Sud, Université Paris-Saclay, CNRS UMR 3348, Orsay, France.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Zaniboni
authors.affiliation: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France. Technological Advances for Genomics and Clinics (TAGC), INSERM U1090, Université de la Méditerranée, Marseille, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Belhocine
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR 3348, Orsay, France. Université Paris Sud, Université Paris-Saclay, CNRS UMR 3348, Orsay, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Da Costa de Jesus
authors.affiliation: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lhermitte
authors.affiliation: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Melania
authors.initials: M
authors.lastname: Tesio
authors.affiliation: INSERM UMR 1163 and CNRS ERL 8654, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Laboratory of Excellence GR-Ex, Imagine Institute and Paris Descartes University, Sorbonne Paris Cité, Paris, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Dussiot
authors.affiliation: CIRI, EVIR Team, INSERM U1111, CNRS UMR 5308, Université de Lyon-1, ENS de Lyon, Lyon, France.
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.affiliation: CIRI, EVIR Team, INSERM U1111, CNRS UMR 5308, Université de Lyon-1, ENS de Lyon, Lyon, France. INSERM U1065, C3M, Equipe "Contrôle Métabolique des Morts Cellulaires," Nice, France.
authors.forename: Els
authors.initials: E
authors.lastname: Verhoeyen
authors.affiliation: Laboratoire des Cellules Souches Hématopoïétiques et Leucémiques, UMR 967, INSERM, Commissariat à l'Energie Atomique, Université Paris Diderot, Université Paris 11, Institut de Radiobiologie Cellulaire et Moléculaire, équipe labellisée Ligue Nationale contre le Cancer, Fontenay-aux-Roses, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Pflumio
authors.affiliation: PRES LUNAM, CHU Angers service des Maladies du Sang et INSERM U892, Angers, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.affiliation: Université Paris 7, Hôpital Saint-Louis, AP-HP, Department of Hematology and Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.affiliation: Technological Advances for Genomics and Clinics (TAGC), INSERM U1090, Université de la Méditerranée, Marseille, France.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Spicuglia
authors.affiliation: Institut Necker Enfants Malades, INSERM U1151, CNRS UMR 8253, Hôpital Necker-Enfants Malades, Paris, France, and Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: Lucienne
authors.initials: L
authors.lastname: Chatenoud
authors.affiliation: Institut Necker Enfants Malades, INSERM U1151, CNRS UMR 8253, Hôpital Necker-Enfants Malades, Paris, France, and Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Gross
authors.affiliation: INSERM UMR 1163 and CNRS ERL 8654, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Laboratory of Excellence GR-Ex, Imagine Institute and Paris Descartes University, Sorbonne Paris Cité, Paris, France. Department of Clinical Hematology, Hôpital Necker, Assistance publique hôpitaux de Paris, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.affiliation: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
authors.affiliation: Institut Curie, PSL Research University, CNRS UMR 3348, Orsay, France. Université Paris Sud, Université Paris-Saclay, CNRS UMR 3348, Orsay, France. vahid.asnafi@aphp.fr jacques.ghysdael@curie.fr.
authors.forename: Jacques
authors.initials: J
authors.lastname: Ghysdael
authors.affiliation: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France. vahid.asnafi@aphp.fr jacques.ghysdael@curie.fr.
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D060966:Clonal Selection, Antigen-Mediated; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell