title: Therapeutic targeting of c-Myc in T-cell acute lymphoblastic leukemia, T-ALL.
abstract: T-ALL patients treated with intensive chemotherapy achieve high rates of remission. However, frequent long-term toxicities and relapses into chemotherapy-refractory tumors constitute major clinical challenges which could be met by targeted therapies. c-MYC is a central oncogene in T-ALL, prompting the exploration of the efficacy of MYC inhibitors such as JQ1 (BET-bromodomain inhibitor), and SAHA (HDAC inhibitor). Using a standardized ex vivo drug screening assay, we show here that JQ1 and SAHA show competitive efficiency compared to inhibitors of proteasome, PI3K/AKT/mTOR and NOTCH pathways, and synergize in combination with Vincristine. We also compared for the first time the in vivo relevance of such associations in mice xenografted with human primary T-ALLs. Our data indicate that although treatments combining JQ1 or SAHA with chemotherapeutic regimens might represent promising developments in T-ALL, combinations will need to be tailored to specific subgroups of responsive patients, the profiles of which still remain to be precisely defined.
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université UM 2, 13288 Marseille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Loosveld
authors.forename: Rémy
authors.initials: R
authors.lastname: Castellano
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Gon
authors.forename: Armelle
authors.initials: A
authors.lastname: Goubard
authors.forename: Thomas
authors.initials: T
authors.lastname: Crouzet
authors.forename: Laurent
authors.initials: L
authors.lastname: Pouyet
authors.forename: Thomas
authors.initials: T
authors.lastname: Prebet
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.forename: Bertrand
authors.initials: B
authors.lastname: Nadel
authors.forename: Yves
authors.initials: Y
authors.lastname: Collette
authors.forename: Dominique
authors.initials: D
authors.lastname: Payet-Bornet
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001381:Azepines / Q000008:administration & dosage; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D009757:Nylons; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000008:administration & dosage; D014230:Triazoles / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D056572:Histone Deacetylase Inhibitors; C489427:MYC protein, human; D009757:Nylons; D016271:Proto-Oncogene Proteins c-myc; D011758:Pyrroles; C585734:SAHA-PIP-delta; D014230:Triazoles