Epigenetic Abnormalities

Abnormalities of DNA methylation are common in malignancy and comprise both global hypomethylation and hypermethyla-tion of CpG islands, resulting in loss of gene expression. Global hypomethylation has been found in patients with CLL, including those with early disease.51'52 A single study demonstrated hypomethylation of the promoter region of the BCL2 gene, but although this study has been quoted as an explanation for elevated BCL2 protein levels in CLL, the extent of hypomethylation did not correlate with BCL2 expression.53 No systematic study of DNA hypermethylation in CLL has been performed. As already discussed, we have found specific hypermethylation in close proximity to the LEU2 gene on 13q14. In another study, hypermethylation of the M27 beta locus on the X chromosome was found in 38 percent of patients with CLL but not in normal controls.54

Telomeres are essential for both the function and stability of normal chromosomes. Repeated cell division results in telomere shortening in cells that lack telomerase. Several studies have documented increased telomerase activity and reduced telom-ere length in advanced CLL as compared with patients with stage A disease (Table 6-5). Both the biological significance and the clinical importance of these findings remain uncertain. Preliminary data using flow FISH have shown that the mean telomere length in cases with unmutated VH genes is significantly shorter than in cases with mutated VH genes despite the unmutated group having higher telomerase activity.55

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