title: Genetic Predisposition to Chronic Lymphocytic Leukemia Is Mediated by a BMF Super-Enhancer Polymorphism.
abstract: Chronic 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.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Radhika
authors.initials: R
authors.lastname: Kandaswamy
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Georgina P
authors.initials: GP
authors.lastname: Sava
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Speedy
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Beà
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Departament d'Anatomía Patològica, Microbiología i Farmacología, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: James B
authors.initials: JB
authors.lastname: Studd
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Migliorini
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Law
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Xose S
authors.initials: XS
authors.lastname: Puente
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Martín-García
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Salaverria
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Gutiérrez-Abril
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Catovsky
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK.
authors.forename: James M
authors.initials: JM
authors.lastname: Allan
authors.affiliation: Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK; Division of Molecular Pathology, The Institute of Cancer Research, London SW7 3RP, UK. Electronic address: richard.houlston@icr.ac.uk.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15; D004742:Enhancer Elements, Genetic; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012306:Risk; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000595707:BCL2 protein, human; C486655:BMF protein, human; D002843:Chromatin; D006657:Histones; D019253:Proto-Oncogene Proteins c-bcl-2; C498143:RELA protein, human; D051996:Transcription Factor RelA