Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers.

Anouk Emadali; Sophie Rousseaux; Juliana Bruder-Costa; Claire Rome; Samuel Duley; Sieme Hamaidia; Patricia Betton; Alexandra Debernardi; Dominique Leroux; Benoit Bernay; Sylvie Kieffer-Jaquinod; Florence Combes; Elena Ferri; Charles Mckenna; Carlo Petosa; Christophe Bruley; Jérôme Garin; Myriam Ferro; Rémy Gressin; Mary Callanan; Saadi Khochbin

doi:10.1002/emmm.201202034

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

* Auteur correspondant

1 BGE - UMR S1038 - Laboratoire de Biologie à Grande Échelle

2 INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble

3 Pôle recherche

4 Service d'onco-hématologie et génétique

5 Department of Chemistry

6 IBS - UMR 5075 - Institut de biologie structurale

7 Service d'hématologie clinique

8 INSERM U823, équipe 7 (Voies Oncogéniques Des Hémopathies Malignes)

INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble

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.

Keywords : Double hit B-cell non-Hodgkin's lymphoma CCDC86 CD40 cancer-testis factor R- CHOP

Type de document :

Article dans une revue

EMBO Molecular Medicine, Wiley Open Access, 2013, 5 (8), pp.1180-95. 〈10.1002/emmm.201202034〉

Domaine :

Sciences du Vivant [q-bio] / Génétique

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http://www.hal.inserm.fr/inserm-00852222
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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

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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

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