Leukemia, Chronic Lymphocytic, Susceptibility To, 3
For a phenotypic description and a discussion of genetic heterogeneity of chronic lymphocytic leukemia (CLL), see 151400.
Clinical FeaturesLynch et al. (2002) described a family in which the father and all 4 of his children had CLL. All of the children were male, and 2 were identical twins. CLL was diagnosed at the age of 77 in the father, at the ages of 56 and 54 in the identical twins, and at the ages of 47 and 39 in the other brothers.
MappingRaval et al. (2007) followed up the family studied by Lynch et al. (2002) and identified additional family members, both affected and unaffected. Genomewide linkage analysis identified a region on chromosome 9 between markers D9S175 and D9S1776 with a nonparametric linkage score of 0.96. High resolution genotyping identified a common haplotype of 707 kb in all affected family members for whom samples were available. The segment of the presumed haplotype included 3 known genes, including DAPK1 (600831), and 11 predicted genes. Based on epigenetic data indicating frequent loss of DAPK1 expression in CLL, Raval et al. (2007) hypothesized that DAPK1 might be the predisposing gene mutated in this family.
Molecular GeneticsIn the CLL allele of affected family members, Raval et al. (2007) identified an A-to-G transition -6531 upstream of the DAPK1 gene promoter on chromosome 9q34 that was not identified in 383 control samples. Screening of 263 additional CLL cases identified one CLL case with the -6531A-G single-nucleotide polymorphism (SNP). Experiments using luciferase reporter constructs, semiquantitative PCR, and transfection with small interfering RNA (siRNA) demonstrated that DAPK1 expression is downregulated by HOXB7 and suggested that the -6531A-G SNP increases the affinity of HOXB7 binding, resulting in stronger repression of DAPK1 from the CLL allele. Bisulfite sequencing of peripheral blood mononuclear cell DNA from affected and unaffected family members for 2 promoter regions showed that both regions were highly methylated in affected family members. Raval et al. (2007) concluded that loss or reduced expression of DAPK1 underlies heritable predisposition to CLL and the majority of sporadic CLL.