Genetic Predisposition to Chronic Lymphocytic Leukemia Is Mediated by a BMF Super-Enhancer Polymorphism.
View/ Open
Date
2016-08-23Author
Kandaswamy, R
Sava, GP
Speedy, HE
Beà, S
Martín-Subero, JI
Studd, JB
Migliorini, G
Law, PJ
Puente, XS
Martín-García, D
Salaverria, I
Gutiérrez-Abril, J
López-Otín, C
Catovsky, D
Allan, JM
Campo, E
Houlston, RS
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
B-Lymphocytes
Cell Line, Tumor
Chromosomes, Human, Pair 15
Chromatin
Humans
Genetic Predisposition to Disease
Adaptor Proteins, Signal Transducing
Proto-Oncogene Proteins c-bcl-2
Histones
Odds Ratio
Risk
Chromosome Mapping
Binding Sites
Protein Binding
Polymorphism, Single Nucleotide
Alleles
Transcription Factor RelA
Leukemia, Lymphocytic, Chronic, B-Cell
Enhancer Elements, Genetic
Genome-Wide Association Study
Genetic Loci
Research team
Cancer Genomics
Molecular & Population Genetics
Language
eng
Date accepted
2016-07-20
License start date
2016-08-11
Citation
Cell reports, 2016, 16 (8), pp. 2061 - 2067
Publisher
CELL PRESS