CLONING OF 2 CANDIDATE TUMOR-SUPPRESSOR GENES WITHIN A 10 KB REGION ON CHROMOSOME 13Q14, FREQUENTLY DELETED IN CHRONIC LYMPHOCYTIC-LEUKEMIA

Previous studies have indicated the presence of a putative tumor suppr essor gene on chromosome 13q14, commonly deleted in patients with B-ce ll chronic lymphocytic leukemia (B-CLL), We have previously defined a minimally deleted region of 130 kb centromeric to the marker D13S272, and constructed a PAC and cosmid contig encompassing this area, In the present study we have made a detailed restriction and transcriptional map of the region of interest, Using these tools we have screened a p anel of 206 primary CLL clones and three cell lines. In five CLL cases we found limited deletions defining the region of interest to an area of no more than 10 kb, Two adjacent genes, termed Leu1 and Leu2 (leuk emia-associated gene 1 and 2), mere mapped to the minimally deleted re gion, with several patients showing deletion borders within these gene s, The Leu1 and Lead genes show little homology to previously publishe d genes at the nucleotide and expected translated amino acid sequence level, Mutational analysis of the Leu1 and 2 genes in 170 CLL samples revealed no small intragenic mutations or point mutations, However, in all cases of 13q14 loss examined, the first exon of both genes, which are only 300 bp apart, were deleted, We conclude that the Leu1 and Le ad genes are strong candidates as tumor suppressor gene(s) involved in B-CLL leukemogenesis.