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

Abstract

SummaryChronic 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.

Super-Enhancer-Driven Transcriptional Dependencies in Cancer

“…Broadly speaking, inappropriate SE formation and function may stem from (i) alterations in cis -regulatory elements (cis-REs) [38, 53, 54], (ii) focal and large-scale chromosomal rearrangements [20, 30, 55–59], and (iii) rewiring of the cellular TF network by viral oncogenes [60–62]. …”

“…Such alterations in cis-REs can also disrupt SEs associated with tumor suppressor genes. In chronic lymphocytic leukemia associated with the 15q15.1 risk locus, a SNP within the intronic SE of the pro-apoptotic gene BMF , disrupts a binding site for the transcription factor RELA , resulting in compromised enhancer activity, reduced BMF expression, and unrestrained anti-apoptotic BCL2 function [53]. Together, these examples illustrate how alterations in cis-REs modulate SE formation by routing tissue-specific TFs to key drivers and repressors of oncogenesis.…”

Long-term Outcomes in Patients with Chronic Lymphocytic Leukemia Treated with Standard Therapy

“…More recently, a study was published showing a decrease in the B cell lymphoma 2 (BCL2)-modifying factor incidence, an antiapoptotic modulator [27]. Genetic differences have been defined, including its clinical consequences amongst said populations, although there is no final explanation [28]. Environmental influencing factors impacting on these dramatic differences are proposed.…”

Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions

“…8 Approximately 40 susceptibility loci associated with CLL have been identifed. [9][10][11][12][13] Most of them are in areas of active chromatin that may regulate genes influencing CLL development. Intriguingly, only a few of these candidate genes are altered in the overt disease (eg, POT1, BCL2, and IRF4).…”

“…14 This difference suggests that susceptibility and driver CLL genes may influence different steps in the development of the disease or, although different, they may target similar pathways (eg, susceptibility variants in TERT and mutations in POT1 may interfere with telomeric function while the susceptibility BMF variant regulates BCL2 expression). 9,[11][12][13]15…”