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dc.contributor.authorKandaswamy, Ren_US
dc.contributor.authorSava, GPen_US
dc.contributor.authorSpeedy, HEen_US
dc.contributor.authorBeà, Sen_US
dc.contributor.authorMartín-Subero, JIen_US
dc.contributor.authorStudd, JBen_US
dc.contributor.authorMigliorini, Gen_US
dc.contributor.authorLaw, PJen_US
dc.contributor.authorPuente, XSen_US
dc.contributor.authorMartín-García, Den_US
dc.contributor.authorSalaverria, Ien_US
dc.contributor.authorGutiérrez-Abril, Jen_US
dc.contributor.authorLópez-Otín, Cen_US
dc.contributor.authorCatovsky, Den_US
dc.contributor.authorAllan, JMen_US
dc.contributor.authorCampo, Een_US
dc.contributor.authorHoulston, RSen_US
dc.date.accessioned2016-08-18T10:00:18Z
dc.date.issued2016-08-11en_US
dc.identifier.citationCell reports, 2016, 16 (8), pp. 2061 - 2067en_US
dc.identifier.issn2211-1247en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/65
dc.identifier.eissn2211-1247en_US
dc.identifier.doi10.1016/j.celrep.2016.07.053en_US
dc.description.abstractChronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10(-13), odds ratio = 1.35), localizes to a super-enhancer defined by extensive histone H3 lysine 27 acetylation in intron 3 of B cell lymphoma 2 (BCL2)-modifying factor (BMF). The rs539846-A risk allele alters a conserved RELA-binding motif, disrupts RELA binding, and is associated with decreased BMF expression in CLL. These findings are consistent with rs539846 influencing CLL susceptibility through differential RELA binding, with direct modulation of BMF expression impacting on anti-apoptotic BCL2, a hallmark of oncogenic dependency in CLL.en_US
dc.formatPrint-Electronicen_US
dc.format.extent2061 - 2067en_US
dc.languageengen_US
dc.language.isoengen_US
dc.subjectB-Lymphocytesen_US
dc.subjectCell Line, Tumoren_US
dc.subjectChromosomes, Human, Pair 15en_US
dc.subjectChromatinen_US
dc.subjectHumansen_US
dc.subjectGenetic Predisposition to Diseaseen_US
dc.subjectAdaptor Proteins, Signal Transducingen_US
dc.subjectProto-Oncogene Proteins c-bcl-2en_US
dc.subjectHistonesen_US
dc.subjectOdds Ratioen_US
dc.subjectRisken_US
dc.subjectChromosome Mappingen_US
dc.subjectBinding Sitesen_US
dc.subjectProtein Bindingen_US
dc.subjectPolymorphism, Single Nucleotideen_US
dc.subjectAllelesen_US
dc.subjectTranscription Factor RelAen_US
dc.subjectLeukemia, Lymphocytic, Chronic, B-Cellen_US
dc.subjectEnhancer Elements, Geneticen_US
dc.subjectGenome-Wide Association Studyen_US
dc.subjectGenetic Locien_US
dc.titleGenetic Predisposition to Chronic Lymphocytic Leukemia Is Mediated by a BMF Super-Enhancer Polymorphism.en_US
dc.typeJournal Article
dcterms.dateAccepted2016-07-20en_US
rioxxterms.versionofrecord10.1016/j.celrep.2016.07.053en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2016-08-11en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfCell reportsen_US
pubs.issue8en_US
pubs.notesNo embargoen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular & Population Genetics
pubs.publication-statusPublisheden_US
pubs.volume16en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamCancer Genomicsen_US
icr.researchteamMolecular & Population Geneticsen_US
dc.contributor.icrauthorHoulston, Richarden_US
dc.contributor.icrauthorLaw, Philipen_US
dc.contributor.icrauthorSava, Georginaen_US


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