title: Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers.
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.
authors.affiliation: CEA, iRTSV, Biologie à Grande Echelle, Grenoble, France.
authors.forename: Anouk
authors.initials: A
authors.lastname: Emadali
authors.forename: Sophie
authors.initials: S
authors.lastname: Rousseaux
authors.forename: Juliana
authors.initials: J
authors.lastname: Bruder-Costa
authors.forename: Claire
authors.initials: C
authors.lastname: Rome
authors.forename: Samuel
authors.initials: S
authors.lastname: Duley
authors.forename: Sieme
authors.initials: S
authors.lastname: Hamaidia
authors.forename: Patricia
authors.initials: P
authors.lastname: Betton
authors.forename: Alexandra
authors.initials: A
authors.lastname: Debernardi
authors.forename: Dominique
authors.initials: D
authors.lastname: Leroux
authors.forename: Benoit
authors.initials: B
authors.lastname: Bernay
authors.forename: Sylvie
authors.initials: S
authors.lastname: Kieffer-Jaquinod
authors.forename: Florence
authors.initials: F
authors.lastname: Combes
authors.forename: Elena
authors.initials: E
authors.lastname: Ferri
authors.forename: Charles E
authors.initials: CE
authors.lastname: McKenna
authors.forename: Carlo
authors.initials: C
authors.lastname: Petosa
authors.forename: Christophe
authors.initials: C
authors.lastname: Bruley
authors.forename: Jérôme
authors.initials: J
authors.lastname: Garin
authors.forename: Myriam
authors.initials: M
authors.lastname: Ferro
authors.forename: Rémy
authors.initials: R
authors.lastname: Gressin
authors.forename: Mary B
authors.initials: MB
authors.lastname: Callanan
authors.forename: Saadi
authors.initials: S
authors.lastname: Khochbin
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D018951:Antigens, CD20 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D006801:Humans; D008223:Lymphoma; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D017434:Protein Structure, Tertiary; D040901:Proteomics; D000069283:Rituximab; D014230:Triazoles / Q000494:pharmacology
chemical_list: C561695:(+)-JQ1 compound; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D001381:Azepines; D014230:Triazoles; D000069283:Rituximab
keywords: CCDC86; CD40; R-CHOP; cancer-testis factor; double-hit B-cell non-Hodgkin's lymphoma