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Triggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemia

2016-09Journal article Restricted access
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dc.contributor.authorTrinquand, Amelie
dc.contributor.authordos Santos, Nuno R.
dc.contributor.authorQuang, Christine Tran
dc.contributor.authorRocchetti, Francesca
dc.contributor.authorZaniboni, Benedetta
dc.contributor.authorBelhocine, Mohamed
dc.contributor.authorde Jesus, Cindy Da Costa
dc.contributor.authorLhermitte, Ludovic
dc.contributor.authorTesio, Melania
dc.contributor.authorDussiot, Michael
dc.contributor.authorCosset, Francois-Loic
dc.contributor.authorVerhoeyen, Els
dc.contributor.authorPflumio, Francoise
dc.contributor.authorIfrah, Norbert
dc.contributor.authorDombret, Herve
dc.contributor.authorSpicuglia, Salvatore
dc.contributor.authorChatenoud, Lucienne
dc.contributor.authorGross, David-Alexandre
dc.contributor.authorHermine, Olivier
dc.contributor.authorMacintyre, Elizabeth
dc.contributor.authorGhysdael, Jacques
dc.contributor.authorAsnafi, Vahid
dc.date.accessioned2017-04-07T15:56:05Z
dc.date.available2017-04-07T15:56:05Z
dc.date.issued2016-09
dc.description.abstractCancer 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.
dc.identifier.doi10.1158/2159-8290.CD-15-0675
dc.identifier.issn2159-8274
dc.identifier.urihttp://hdl.handle.net/10400.1/9312
dc.language.isoeng
dc.peerreviewedyes
dc.relation.isbasedonWOS:000383356400023
dc.titleTriggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemia
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage985
oaire.citation.issue9
oaire.citation.startPage972
oaire.citation.titleCancer Discovery
oaire.citation.volume6
rcaap.rightsrestrictedAccess
rcaap.typearticle

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