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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Alleles
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Binding Sites
  • Cell Line, Tumor
  • Chromatin / chemistry
  • Chromatin / metabolism
  • Chromosome Mapping
  • Chromosomes, Human, Pair 15
  • Enhancer Elements, Genetic*
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Odds Ratio
  • Polymorphism, Single Nucleotide*
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Risk
  • Transcription Factor RelA / genetics*
  • Transcription Factor RelA / metabolism


  • Adaptor Proteins, Signal Transducing
  • BCL2 protein, human
  • BMF protein, human
  • Chromatin
  • Histones
  • Proto-Oncogene Proteins c-bcl-2
  • RELA protein, human
  • Transcription Factor RelA