Leukemia, Chronic Lymphocytic, Susceptibility To, 4

For a phenotypic description and discussion of genetic heterogeneity of chronic lymphocytic leukemia (CLL), see 151400.

Di Bernardo et al. (2008) conducted a genomewide association study of 299,983 tagging single-nucleotide polymorphisms (SNPs) for CLL and performed validation in 2 additional series totaling 1,529 cases and 3,115 controls. The authors identified 6 previously unreported CLL risk alleles. Di Bernardo et al. (2008) found the strongest association with rs872071 and rs9378805, which map to a 97-kb block of linkage disequilibrium on chromosome 6p25.3 encompassing the IRF4 gene (601900). The SNP rs872071 maps within the 3-prime untranslated region (UTR) of IRF4, and rs9378805 maps 10 kb centromeric to the 3-prime UTR of IRF4. The overall estimate of effect associated with rs872071 was an odds ratio trend of 1.54 with a 95% confidence interval of 1.41 to 1.69 and a P value of 1.91 x 10(-20). The genotype at rs872071 was sufficient to capture all of the locus variation. IRF4 is a strong candidate gene for a CLL susceptibility a priori, being a key regulator of lymphocyte development and proliferation. Di Bernardo et al. (2008) investigated the relationship between rs872071 genotype and mRNA expression in Epstein-Barr virus (EBV)-transformed lymphocytes. Expression was significantly associated with genotype in a dose-dependent fashion (P = 0.042), with lower expression associated with risk alleles. Di Bernardo et al. (2008) argued that this observation is consistent with a model in which the causal variant influences risk by arresting transition of memory B cells through decreased IRF4 expression.

Using a set of SNP markers, Crowther-Swanepoel et al. (2010) generated a fine-scale map of 6p25.3 and narrowed the signal for association with CLL to an 18-kb DNA segment within the 3-prime UTR of IRF4. Resequencing this segment in European subjects identified 55 common polymorphisms, including 13 highly correlated candidate causal variants. In a large case-control study, it was shown that all but 4 variants could be excluded with 95% confidence. These 4 SNPs mapped to a 3-kb region of the 3-prime UTR of IRF4, consistent with the causal basis of the association being differential IRF4 expression.

New Zealand Black (NZB) mice naturally develop late-onset CLL, typically around 12 months of age, with the malignant CLL clones derived from B1 cells. Ma et al. (2013) generated Irf4 heterozygous mutant mice on an NZB background (NZB Irf4 +/- mice). They found that CLL cells could be detected at 3 months of age in some NZB Irf4 +/- mice, and that 80% of NZB Irf4 +/- mice developed CLL by 5 months of age. Irf4 +/- B1 cells exhibited prolonged survival, accelerated self-renewal, and defects in differentiation. NZB Irf4 +/- cells were resistant to apoptosis, but high levels of Irf4 inhibited their survival, an effect also seen in human leukemia cell lines. High levels of Irf4 suppressed Akt (164730) activity in a manner independent of the Irf4 DNA-binding domain. Ma et al. (2013) concluded that there is a causal relationship between low levels of IRF4 and development of CLL and that IRF4 is a regulator of CLL pathogenesis.