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genes

genes

the initiating events in leukemogenesis include the investigation of cases of familial CLL,58-60 mutational analysis of candidate genes such as CD79B (as discussed above), and global gene expression studies using subtractive hybridization techniques or cDNA arrays.61

In most human tumors, genetic abnormalities accumulate during the course of the disease and contribute to disease progression and drug resistance.

Sequential cytogenetic and interphase FISH studies have demonstrated clonal evolution in 10 to 20 percent of cases13,62 and confirmed that deletions of chromosomes 6q, 11q, and 17p are the most frequent secondary abnormalities.63,64 Trisomy 12 is almost invariably a primary cytogenetic abnormality in CLL, but interphase FISH has shown that only part of the leukemic clone carries the additional copy of chromosome 12.65 In patients with CLL who develop a diffuse large-cell lymphoma (Richter syndrome), the new clone may be either derived from the CLL clone or unrelated. In those cases in which the large-cell lymphoma is clonally related to CLL, studies on small numbers of patients have not shown a consistent transforming event.66

The mechanisms responsible for both genomic abnormalities and genetic instability in CLL are poorly understood. Both p53 and ATM mutations are associated with genomic instability, but these mutations are usually late events in CLL. Trinucleotide repeat sequences have been found close to the chromosome breakpoints in cases with deletion of 11q, and these may be responsible for increased chromosome fragility.67 Microsatellite instability appears to be rare in CLL.68 In experimental studies telomere shortening correlates with genomic instability, including the formation of dicentric chromosomes, but the significance of shortened telomeres in advanced CLL is unclear.

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