FREQUENT DELETION OF P16(INK4A)IMTS1 AND P15(INK4B)IMTS2 IN PEDIATRICACUTE LYMPHOBLASTIC-LEUKEMIA

The tandemly linked p16(INK4a)MTS1 and p15(INK4b)/MTS2 genes on chromo some 9, band p21 encode proteins that function as specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. This locus undergoes frequent bi-allelic deletion in human cancer cell lines, suggesting th at the encoded proteins may function as tumor suppressors. However, mo re recent analysis of primary tumor samples has shown a much lower fre quency of abnormalities affecting this region, raising doubt over the importance of these proteins in human malignancies, Hemizygous deletio ns and rearrangements of chromosome 9, band p21, are among the most fr equent cytogenetic abnormalities detected in pediatric acute lymphobla stic leukemia (ALL), occurring in approximately 10% of cases. To deter mine if the p16(INK4a)/p15(INK4b) locus might be the target of these c hromosomal lesions, we analyzed both genes in primary clinical samples from 43 pediatric ALL patients using interphase fluorescence in situ hybridization, Southern blot analysis, and the polymerase chain reacti on. Deletions of p16(INK4a)/p15(INK4b) were identified in 18 of 20 cas es with cytogenetically observed abnormalities of 9p and 5 of 23 with apparently normal chromosomes 9p, with the majority containing bi-alle lic deletions (16 homozygous/7 hemizygous). Although most homozygous d eletions involved both genes, Southern blot analysis showed an interst itial deletion in a single case that was confined to p16(INK4a), sugge sting that p15(INK4b) was not the critical target gene in this case. S equence analysis of both p16(INK4a) and p15(INK4b) in all seven cases with hemizygous deletions failed to show mutations within the coding r egions of the retained alleles. In this select group of patients, dele tion of p16(INK4a)/p15(INK4b) was associated with T-cell phenotype, no nhyperdiploid karyotype (<50 chromosomes), and poor event-free surviva l. These findings indicate that deletion of the p16(INK4a)/p15(INK4b) locus is one of the most common genetic abnormalities so far detected in pediatric ALL, and that loss of one or more of these cell cycle kin ase inhibitors is important in leukemogenesis. (C) 1995 by The America n Society of Hematology.