DESCRIPTION: B-cell chronic lymphocytic leukemia (BCLL) is the most common hematological malignancy in the Western World. Morbidity and mortality result from slow progression of the disease which often results in reduced immunocompetence and bone marrow failure. Cytogenetic analysis of tumor cells reveals that up to half of these leukemias show structural rearrangements involving chromosome 13. Although these may be deletions, or reciprocal translocations, chromosome band 13q14 is always involved. Furthermore, these chromosome 13 abnormalities frequently occur as the only structural chromosome change in the tumor cells. This fact, together with the consistency of the abnormality in different tumors, indicates that there is a gene(s) located in 13q14 which is responsible for the development of BCLL. The applicants have previously shown that small deletions are associated with the chromosome translocations seen in a number of different tumors and have now defined a 500 Kb region which is commonly deleted in all cases. A wider study of tumors shows that this region is homozygously deleted in many cases. This observation argues strongly for the presence of a tumor suppressor gene in this region. Both a yeast artificial chromosome (YAC) contig and a bacterial artificial chromosome contig (BAC) have now been constructed across the smallest deleted region We will use these YACs and BACs to isolated candidate genes from the region using a combination of differential display, exon-trapping, CDNA screening and candidate gene analysis. To verify their involvement in tumorigenesis, the structure of the genes will be established and direct sequencing and single strand conformation polymorphism analysis will be used to identify mutations in tumor cells. By identifying and characterizing genes which are responsible for BCLL it will eventually be possible to assess their value in the detection of relapse in patients with BCLL following treatment. Also as a result of an improved understanding of the genetic events which give rise to BCLL, it may eventually be possible to design novel gene therapeutic approaches towards treating this disorder.
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