期刊
EMBO MOLECULAR MEDICINE
卷 5, 期 8, 页码 1180-1195出版社
WILEY
DOI: 10.1002/emmm.201202034
关键词
cancer-testis factor; CCDC86; CD40; double-hit B-cell non-Hodgkin's lymphoma; R-CHOP
资金
- INSERM
- CEA
- Universite Joseph Fourier
- CHU-Grenoble
- INCa-DHOS Translational Research program
- 'ARC subvention libre' programs
- ARC
- Fondation de France
- Ligue Contre le Cancer (Comite Isere et Haute-Savoie)
- Partner University Fund
- ARC (Association pour le Recherche sur le Cancer)
- INCa (Institut National du Cancer)
- INCa-DHOS program
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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