ABSTRACT
I. INTRODUCTION B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults. Despite the high incidence, the knowledge on the genomic aberrations underlying B-CLL pathogenesis is still limited. This is mainly related to the low in-vitro mitotic activity of the tumor cells, which has made conventional cytogenetic studies by chromosome banding difficult. On the other hand, analyses based on molecular genetic techniques such as South ern blot analysis or polymerase chain reaction (PCR) have been limited by the fact that candidate genes are known only for few chromosome regions affected in B-CLL. By fluorescence in-situ hybridization (FISH) genomic abnormalities can be detected on the single cell level in nondividing cells, circumventing the need to obtain metaphase chromo somes from B-CLL cells. The genomic regions can be detected with DNA probes available from genome-wide libraries without the need of prior candidate gene identification. By FISH with a disease-specific probe set aberrations can now be detected in more than 80% of B-CLL cases. In contrast to other types of low-grade lymphoma the by far most frequent type of genomic aberration in B-CLL are deletions. The most frequent deletion cluster regions involve band 13ql4, followed by Ilq22-q23, 17pl3, and 6q21. Common gains of chromosomal material are trisomies 12q, 8q, and 3q. Translocations involving the im munoglobulin heavy chain gene locus (IgH) at 14q32, which are frequently observed in other types of lymphoma, are rare events in B-CLL. Genes targeted by the aberrations in B-CLL appear to be p53 in band 17pl3 and ATM in a subset of cases with Ilq22-q23 deletions. However, for most of the frequently affected genomic regions in B-CLL, the
search for candidate genes is ongoing. In addition to the delineation of critical regions, FISH allowed the accurate evaluation of the incidence of genomic aberrations in B-CLL. This provided the valid basis for a correlation of the abnormalities with clinical phenotype and survival. Deletions 17pl3 (p53) and Ilq22-q23 have proven to be among the most important independent prognostic factors identifying subgroups of patients with rapidly progressive disease and inferior survival. In addition, deletion 17pl3 (p53) has been shown to predict for nonresponse to therapy with purine analogs. The study of genomic aberra tions may lead to a better understanding of the molecular pathogenesis of the disease. Furthermore, the prognostic significance of these aberrations may have implications for a better risk-adapted management of B-CLL patients in the near future.
