Therapeutic targeting of c-Myc in T-cell acute lymphoblastic leukemia, T-ALL.

// Marie Loosveld 1,2,3,4* , Remy Castellano 5* , Stephanie Gon 1,2,3* , Armelle Goubard 5 , Thomas Crouzet 1,2,3 , Laurent Pouyet 5 , Thomas Prebet 6 , Norbert Vey 6 , Bertrand Nadel 1,2,3* , Yves Collette 5* , Dominique Payet-Bornet 1,2,3* 1 Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Universite UM 2, 13288 Marseille, France 2 INSERM UMR 1104 3 CNRS UMR 7280, 13288 Marseille, France 4 Laboratoire Hematologie, APHM, Marseille, France 5 Centre de Recherche en Cancerologie de Marseille (CRCM) Inserm UMR 1068; Institut Paoli-Calmettes; Aix-Marseille Universite UM 105; CNRS UMR 7258, Marseille, France 6 Departement d’hematologie, Institut Paoli-Calmettes, Marseille, France. * contributed equally to this work Correspondence: Dominique PAYET-BORNET , email: // Bertrand NADEL , email: // Keywords : T-ALL, MYC, JQ1, SAHA Received : March 20, 2014 Accepted : March 26, 2014 Published : March 27, 2014 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.