Molecular analysis of nonrandom 8q12 deletions in acute lymphoblastic leukemia: identification of two candidate genes

Acute lymphoblastic leukemia is the most common malignancy in childhood. High-resolution allelotyping performed in our laboratory showed new chromosomal sites of nonrandom deletions. We have focused our work on 8q12 deletions, which we have found in about 4% of patients (eight of 205 informative cases). These deletions were of small size (less than 1 Mb) in all but one patient, and the deleted region common to all patients was delineated between two microsatellite markers (D8S1113 and D8S1763). This region was sequenced entirely from two overlapping bacterial artificial chromosomes. The common deleted region (120 kb) had a low GC content (37%), was composed more than 50% of LINE sequences, and contained only two candidate genes. The centromeric deletion borders were clustered within an interval of 33 kb between two microsatellite markers. This interval contains the first exon of an HMG-1-related gene (KIAA0808) and a putative gene, DL8q12, predicted to encode a protein with 231 amino acid residues with no homolog in protein databases. Analysis of the available mRNA from lymphoblastic cells of two patients with 8q12 deletions using common polymorphisms in the 3' UTR of KIAA0808 showed monoallelic expression of this gene. Identification of a biallelic polymorphism in the first exon of DL8q12 showed that this gene was deleted in two of four informative cases. Sequencing of the exons of both genes from all patients with 8q12 deletions did not show any mutation, which suggests that neither of these genes behaves as a classic tumor suppressor gene.