MOLECULAR CYTOGENETIC ANALYSIS OF B-CELL CHRONIC LYMPHOCYTIC-LEUKEMIA

The genetic alterations underlying tl ie pathogenesis of B-cell chroni c lymphocytic leukemia (B-CLL) are difficult to assess. Cytogenetic st udies ape hindered by the low in vitro mitotic activity of the tumor c ells and the limited resolution of chromosome banding. Molecular genet ic analyses are hampered by nonclonal cells contained in the specimens and by the limited knowledge of candidate genes involved. As a comple ment to cytogenetic and molecular genetic techniques, fluorescence in situ hybridization (FISH) has proven powerful in the molecular cytogen etic analysis of B-CLL. FISH allows the detection of aberrations such as trisomies, deletions, and translocation breakpoints on the single c ell level in dividing as well as non-dividing cells without the prereq uisite of detailed physical maps or knowledge of involved genes. As de tected by the interphase cytogenetic FISH approach, the most common ch romosome abnormalities of B-CLL are deletions in band 13q14, followed by deletions in 11q22-q23, trisomy 12, deletions in 17p13, and deletio ns in 6q21. Abnormalities in 17p13 seem to involve the TP53 tumor supp ressor gene, but as yet no candidate genes have been identified for th e other frequent aberrations. Toward the identification of such genes by positional cloning, FISH can be applied for detailed aberration map ping at the molecular level. Furthermore, the accurate detection of ch romosome aberrations in B-CLL by FISH provides a valid basis for the E valuation of their prognostic significance. Inactivation of TP53 in 17 p13 and deletions in 11q22-q23 have already been shown to be among the most important independent prognostic factors. Genetic abnormalities may eventually provide biological parameters, allowing a risk assessme nt for individual patients at the time of diagnosis of this clinically heterogeneous disease.