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Cell Rep. 2016 Aug 23;16(8):2061-2067. doi: 10.1016/j.celrep.2016.07.053. Epub 2016 Aug 11.

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

Author information

1
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
2
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
3
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.
4
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
5
Division of Molecular Pathology, The Institute of Cancer Research, London SW7 3RP, UK.
6
Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK.
7
Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain.
8
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.

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.

PMID:
27524613
PMCID:
PMC4999417
DOI:
10.1016/j.celrep.2016.07.053
[Indexed for MEDLINE]
Free PMC Article

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