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

Abstract

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.

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

“…TOX is located on 8q12.1 and encodes a DNAbinding factor that is required for the development of many cell lineages in the immune system, such as CD4 (þ) T cells, natural killer T cells, and regulatory T cells (43,44) and may contribute to the observed arrest of B-cell differentiation in PCNSL. Deletions of TOX in one previous case of PCNSL (18) and in 4% of childhood acute lymphatic leukemias have been reported (45). HDAC9, which is a unique gene located in the 7p21.1 amplified region, encodes a member of the class IIa histone deacetylase (HDAC) enzyme family, which is involved in chromatin condensation and transcriptional repression (46).…”

Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma

“…TOX has been reported to be also deleted in 4% (8/205) of childhood acute lymphatic leukemia. 39 Further candidate genes within the 8q12.1-8q12.2 region are the potential oncogene CA8, which promotes growth, proliferation and invasion of carcinoma cells, [40][41][42] and the RAB2A gene encoding the ras-related rab2.…”

ST18 is a breast cancer tumor suppressor gene at human chromosome 8q11.2

“…In search of a candidate gene within this region, we detected ST18. To date, several other genes within the 8q11-q12 region were identified, which may also be involved in the tumorigenesis of different types of cancer, including acute lymphoblastic leukemia (Bardet et al, 2002) and lipoblastoma (Astrom et al, 2000). Recently, the gene RB1CC1, located on 8q11.2, was found to be frequently mutated in human breast cancer (Chano et al, 2002).…”