These authors contributed equally to this work.
Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers
Article first published online: 4 JUL 2013
Copyright © 2013 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 8, pages 1180–1195, August 2013
How to Cite
Emadali, A., Rousseaux, S., Bruder-Costa, J., Rome, C., Duley, S., Hamaidia, S., Betton, P., Debernardi, A., Leroux, D., Bernay, B., Kieffer-Jaquinod, S., Combes, F., Ferri, E., McKenna, C. E., Petosa, C., Bruley, C., Garin, J., Ferro, M., Gressin, R., Callanan, M. B. and Khochbin, S. (2013), Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers. EMBO Mol Med, 5: 1180–1195. doi: 10.1002/emmm.201202034
See accompanying article 10.1002/emmm.201303018
- Issue published online: 5 AUG 2013
- Article first published online: 4 JUL 2013
- Manuscript Accepted: 21 MAY 2013
- Manuscript Revised: 17 MAY 2013
- Manuscript Received: 8 NOV 2012
- Université Joseph Fourier and CHU-Grenoble
- cancer-testis factor;
- double-hit B-cell non-Hodgkin's lymphoma;
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.