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Genetic Predisposition to Chronic Lymphocytic Leukemia Is Mediated by a BMF Super-Enhancer Polymorphism

Lookup NU author(s): Professor James Allan

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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 x 10(-13), odds ratio = 1.35), localizes to a superenhancer 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.

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Author(s): Kandaswamy R, Sava GP, Speedy HE, Beà S, Martin-Subero JI, Studd JB, Migliorini G, Law PJ, Puente XS, Martín-García D, Salaverria I, Gutiérrez-Abrill J, López-Otín C, Catovsky D, Allan JM, Campo E, Houlston RS

Publication type: Article

Publication status: Published

Journal: Cell Reports

Year: 2016

Volume: 16

Issue: 8

Pages: 2061-2067

Online publication date: 11/08/2016

Acceptance date: 20/07/2016

Date deposited: 18/10/2016

ISSN (electronic): 2211-1247

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.celrep.2016.07.053

DOI: 10.1016/j.celrep.2016.07.053

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