title: A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma.
abstract: Dysregulated expression of factors that control protein synthesis is associated with poor prognosis of many cancers, but the underlying mechanisms are not well defined. Analysis of the diffuse large B-cell lymphoma (DLBCL) translatome revealed selective upregulation of mRNAs encoding anti-apoptotic and DNA repair proteins. We show that enhanced synthesis of these proteins in DLBCL is mediated by the relief of repression that is normally imposed by structure in the 5'-untranslated regions of their corresponding mRNAs. This process is driven by signaling through mammalian target of rapamycin, resulting in increased synthesis of eukaryotic initiation factor (eIF) 4B complex (eIF4B), a known activator of the RNA helicase eIF4A. Reducing eIF4B expression alone is sufficient to decrease synthesis of proteins associated with enhanced tumor cell survival, namely DAXX, BCL2 and ERCC5. Importantly, eIF4B-driven expression of these key survival proteins is directly correlated with patient outcome, and eIF4B, DAXX and ERCC5 are identified as novel prognostic markers for poor survival in DLBCL. Our work provides new insights into the mechanisms by which the cancer-promoting translational machinery drives lymphomagenesis.
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: E
authors.initials: E
authors.lastname: Horvilleur
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: T
authors.initials: T
authors.lastname: Sbarrato
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: K
authors.initials: K
authors.lastname: Hill
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: R V
authors.initials: RV
authors.lastname: Spriggs
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Screen
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Goodrem
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: K
authors.initials: K
authors.lastname: Sawicka
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: L C
authors.initials: LC
authors.lastname: Chaplin
authors.affiliation: INSERM UMR 1037-CRCT-Equipe 5 CHU Rangueil Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Touriol
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: G
authors.initials: G
authors.lastname: Packham
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: K N
authors.initials: KN
authors.lastname: Potter
authors.affiliation: Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Dirnhofer
authors.affiliation: Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: M J S
authors.initials: MJ
authors.lastname: Dyer
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Bushell
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: M
authors.initials: M
authors.lastname: MacFarlane
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: A E
authors.initials: AE
authors.lastname: Willis
mesh_terms: D020121:5' Untranslated Regions; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D020121:5' Untranslated Regions; D039642:Eukaryotic Initiation Factors; D012333:RNA, Messenger; C031799:eIF-4B