Project: Research project

Project Details


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.
StatusNot started


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