Oncotarget

Research Papers:

Therapeutic Targeting of c-Myc in T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Marie Loosveld, Rémy Castellano, Stéphanie Gon, Armelle Goubard, Thomas Crouzet, Laurent Pouyet, Thomas Prebet, Norbert Vey, Bertrand Nadel, Yves Collette and Dominique Payet-Bornet _

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Oncotarget. 2014; 5:3168-3172. https://doi.org/10.18632/oncotarget.1873

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Abstract

Marie Loosveld1,2,3,4*, Rémy Castellano5*, Stéphanie Gon1,2,3*, Armelle Goubard5, Thomas Crouzet1,2,3, Laurent Pouyet5, Thomas Prebet6, Norbert Vey6, Bertrand Nadel1,2,3*, Yves Collette5*, Dominique Payet-Bornet1,2,3*

1 Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université UM 2, 13288 Marseille, France

2 INSERM UMR 1104

3 CNRS UMR 7280, 13288 Marseille, France

4 Laboratoire Hématologie, APHM, Marseille, France

5 Centre de Recherche en Cancérologie de Marseille (CRCM) Inserm UMR 1068; Institut Paoli-Calmettes; Aix-Marseille Université UM 105; CNRS UMR 7258, Marseille, France

6 Département d’hématologie, 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.


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