Childhood acute lymphoblastic leukemia: is there a tumor suppressor gene in chromosome 12p12.3?

Abstract

Cytogenetic deletions on the short arm of chromosome 12 are common, recurring alterations found in a wide range of hematological neoplasias, including childhood acute lymphoblastic leukemia (ALL), the most frequent pediatric malignancy. This loss of genetic material suggests the presence of a tumor suppressor gene playing an important role in growth regulation or in the differentiation of hematopoietic stem cells. In order to substantiate this hypothesis and determine the chromosomal location of this putative gene, we and others have applied a deletion mapping strategy based on the detection of loss of heterozygosity (LOH) at specific genomic loci in leukemic cells. Hemizygous deletions at chromosome 12p12.3 were observed in childhood B cell precursor ALL, and proved to be one of the most frequent genetic alterations seen in this disease. The shortest region of overlapping deletions (SRO) was delimited by the markers D12S89 (distal) and D12S358 (proximal), separated by a genetic interval of approximately 3 cM. LOH in the same region in other hematological diseases, as well as in a variety of solid tumors, suggests either the presence of several tumor suppressor genes or the existence of a single gene with a wide range of activity. This genetic interval contains two known genes: TEL/ETV6, an ets-like transcription factor, and the cyclin-dependant kinase inhibitor, p27/kip1. Accumulating evidence suggests that an as yet unidentified tumor suppressor gene is closely linked to these two genes. Long-range restriction mapping of the SRO region allowed the construction of a approximately 750 kb physical map containing 4 known genes, 7 STSs, 3 chromosome 12 ESTs and 8 CpG islands. The construction of a 12p12.3 framework map is a crucial step towards the identification of candidate genes and should provide a valuable tool for the characterization of transcriptional units.