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Journal articles
Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers.: CYCLON-induced Rituximab resistance
Anouk Emadali
1
Sophie Rousseaux
2
Juliana Bruder-Costa
2
Claire Rome
2
Samuel Duley
2
Sieme Hamaidia
2, 3
Patricia Betton
2
Alexandra Debernardi
2
Dominique Leroux
2, 4
Benoit Bernay
1
Sylvie Kieffer-Jaquinod
1
Florence Combes
1
Elena Ferri
5
Charles Mckenna
5
Carlo Petosa
6
Christophe Bruley
1
Jérôme Garin
1
Myriam Ferro
1
Rémy Gressin
2, 7
Mary Callanan
8, *
Saadi Khochbin
2
*
Corresponding author
8
INSERM U823, équipe 7 (Voies Oncogéniques Des Hémopathies Malignes)
INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble
Samuel Duley 2
Author
Sieme Hamaidia 2, 3
Author
Patricia Betton 2
Author
Alexandra Debernardi 2
Author
Dominique Leroux 2, 4
Author
Benoit Bernay 1
Author
Sylvie Kieffer-Jaquinod 1
Author
Florence Combes 1
Author
Elena Ferri 5
Author
Charles E. Mckenna 5
Author
Carlo Petosa 6
Author IdHAL : carlo-petosa ORCID : https://orcid.org/0000-0002-9975-1167
Christophe Bruley 1
Author
Jérôme Garin 1
Author
Myriam Ferro 1
Author
Rémy Gressin 2, 7
Author
Mary B. Callanan 8
Correspondent author
Saadi Khochbin 2
Author
1
BGE - UMR S1038 - Laboratoire de Biologie à Grande Échelle (17, Rue des Martyrs 38054 Grenoble cedex 09 - France)
- IRIG - Institut de Recherche Interdisciplinaire de Grenoble : DRF/IRIG/DS (France)
- DRF (CEA) - Direction de Recherche Fondamentale (CEA) : DRF/IRIG (Direction de Recherche Fondamentale
Fundamental Research Division
CEA Saclay
91191 Gif-sur-Yvette
- France)
- CEA - Commissariat à l'énergie atomique et aux énergies alternatives (Centre de Saclay Centre de Grenoble Centre de Cadarache etc - France)
- DRF (CEA) - Direction de Recherche Fondamentale (CEA) : DRF/IRIG (Direction de Recherche Fondamentale
Fundamental Research Division
CEA Saclay
91191 Gif-sur-Yvette
- France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1038 (101, rue de Tolbiac, 75013 Paris - France)
- UGA [2016-2019] - Université Grenoble Alpes [2016-2019] (38058 Grenoble cedex - France)
2
INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble (Institut Albert Bonniot, BP170, 38042 Grenoble Cedex 9 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U823 (101, rue de Tolbiac, 75013 Paris - France)
- EFS (France)
- CHU Grenoble (France)
- UJF - Université Joseph Fourier - Grenoble 1 (BP 53 - 38041 Grenoble Cedex 9 - France)
3
Pôle recherche (Grenoble - France)
- UJF - Université Joseph Fourier - Grenoble 1 (BP 53 - 38041 Grenoble Cedex 9 - France)
- CHU Grenoble (France)
4
Service d'onco-hématologie et génétique (Plateforme hospitalière de génétique moléculaire des tumeurs, Pôle de biologie, Grenoble - France)
- CHU Grenoble (France)
5
Department of Chemistry (Los Angeles, California - United States)
- USC - University of Southern California (Los Angeles, CA, 90089-0484, USA - United States)
6
IBS - UMR 5075 - Institut de biologie structurale (Institut de Biologie Structurale, 71 avenue des martyrs, CS 10090, 38044 Grenoble Cedex 9 - France)
- UGA [2016-2019] - Université Grenoble Alpes [2016-2019] (38058 Grenoble cedex - France)
- CNRS - Centre National de la Recherche Scientifique : UMR5075 / UPR9015 (France)
- IRIG - Institut de Recherche Interdisciplinaire de Grenoble : DRF/IRIG/DBSC (France)
- DRF (CEA) - Direction de Recherche Fondamentale (CEA) : DRF/IRIG (Direction de Recherche Fondamentale
Fundamental Research Division
CEA Saclay
91191 Gif-sur-Yvette
- France)
- CEA - Commissariat à l'énergie atomique et aux énergies alternatives (Centre de Saclay Centre de Grenoble Centre de Cadarache etc - France)
- DRF (CEA) - Direction de Recherche Fondamentale (CEA) : DRF/IRIG (Direction de Recherche Fondamentale
Fundamental Research Division
CEA Saclay
91191 Gif-sur-Yvette
- France)
8
INSERM U823, équipe 7 (Voies Oncogéniques Des Hémopathies Malignes) (France)
- INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble (Institut Albert Bonniot, BP170, 38042 Grenoble Cedex 9 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U823 (101, rue de Tolbiac, 75013 Paris - France)
- EFS (France)
- CHU Grenoble (France)
- UJF - Université Joseph Fourier - Grenoble 1 (BP 53 - 38041 Grenoble Cedex 9 - France)
Abstract : Immuno-chemotherapy elicit high response rates in B-cell non-Hodgkin lymphoma but heterogeneity in response duration is observed, with some patients achieving cure and others showing refractory disease or relapse. Using a transcriptome-powered targeted proteomics screen, we discovered a gene regulatory circuit involving the nuclear factor CYCLON which characterizes aggressive disease and resistance to the anti-CD20 monoclonal antibody, Rituximab, in high-risk B-cell lymphoma. CYCLON knockdown was found to inhibit the aggressivity of MYC-overexpressing tumours in mice and to modulate gene expression programs of biological relevance to lymphoma. Furthermore, CYCLON knockdown increased the sensitivity of human lymphoma B cells to Rituximab in vitro and in vivo. Strikingly, this effect could be mimicked by in vitro treatment of lymphoma B cells with a small molecule inhibitor for BET bromodomain proteins (JQ1). In summary, this work has identified CYCLON as a new MYC cooperating factor that autonomously drives aggressive tumour growth and Rituximab resistance in lymphoma. This resistance mechanism is amenable to next-generation epigenetic therapy by BET bromodomain inhibition, thereby providing a new combination therapy rationale for high-risk lymphoma.
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Journal articles
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https://www.hal.inserm.fr/inserm-00852222
Contributor : Samuel Duley <>
Submitted on : Tuesday, August 20, 2013 - 11:55:25 AM
Last modification on : Tuesday, July 27, 2021 - 9:06:02 AM
Long-term archiving on: : Thursday, November 21, 2013 - 4:14:00 AM
Contributor : Samuel Duley <>
Submitted on : Tuesday, August 20, 2013 - 11:55:25 AM
Last modification on : Tuesday, July 27, 2021 - 9:06:02 AM
Long-term archiving on: : Thursday, November 21, 2013 - 4:14:00 AM
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emmm201202034.pdf
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Identifiers
- HAL Id : inserm-00852222, version 1
- PUBMED : 23828858
- DOI : 10.1002/emmm.201202034
Citation
Anouk Emadali, Sophie Rousseaux, Juliana Bruder-Costa, Claire Rome, Samuel Duley, et al.. Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers.: CYCLON-induced Rituximab resistance. EMBO Molecular Medicine, Wiley Open Access, 2013, 5 (8), pp.1180-95. ⟨10.1002/emmm.201202034⟩. ⟨inserm-00852222⟩
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