Genetic predisposition to chronic lymphocytic leukemia is mediated by a BMF super-enhancer polymorphism

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...

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Detalhes bibliográficos
Autores: Kandaswamy, Radhika, Sava, Georgina P., Speedy, Helen E., Beà Bobet, Sílvia M., Martín-Subero, José Ignacio, Studd, James B., Migliorini, Gabriele, Law, Philip J., Puente, Xose S., Martín García, David, Salaverria Frigola, Itziar, Gutiérrez-Abril, Jesús, López-Otin, Carlos, Catovsky, Daniel, Allan, James M., Campo Güerri, Elias, Houlston, Richard S.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/119703
Acesso em linha:https://hdl.handle.net/2445/119703
Access Level:acceso abierto
Palavra-chave:Leucèmia limfocítica crònica
Cèl·lules B
Genètica humana
Limfòcits
Factors de transcripció
Chronic lymphocytic leukemia
B cells
Human genetics
Lymphocytes
Transcription factors
Descrição
Resumo: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.

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