FREQUENT DELETION OF CHROMOSOME 12P12.3 IN CHILDREN WITH ACUTE LYMPHOBLASTIC-LEUKEMIA

Cytogenetic deletions of the short arm of chromosome 12 are common rec urring alterations found in a wide range of haematological neoplasias, including childhood acute lymphoblastic leukaemia (ALL), the most fre quent paediatric malignancy. Such a loss of genetic material suggests the presence of a tumour suppressor gene which plays an important role in growth regulation or in the differentiation of haemopoietic stem c ells. To substantiate this hypothesis and to determine more precisely the chromosomal location of this putative gene, we applied a deletion mapping strategy based on the detection of loss of heterozygosity (LOH ) at specific genomic loci in tumour cells. 13 polymorphic markers wer e used to screen DNA samples from 20 children with ALL, LOHs at 12p12. 3 were observed in almost 50% of informative B-cell precursor ALL,pati ents analysed. This is one of the most frequent genetic alterations fo und in this disease. A common region of LOH was delimited by the marke rs D12S89 (distal) and D12S358 (proximal), separated by a genetic inte rval of approximately 3 cM. We refined the position of the putative 12 p tumour suppressor gene to a physical interval of <1.3 Mb, a crucial step towards the identification of candidate genes. A yeast artificial chromosome clone contig that spans the entire critically deleted regi on includes two known genes: TEL, a member of the ets family of transc ription factors, and p27(KIP1), a cyclin-dependent kinase inhibitor.