Frequent deletion of p16INK4a/MTS1 and p15INK4b/MTS2 in pediatric acute lymphoblastic leukemia

Abstract

The tandemly linked p16INK4aMTS1 and p15INK4b/MTS2 genes on chromosome 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 that the encoded proteins may function as tumor suppressors. However, more recent analysis of primary tumor samples has shown a much lower frequency of abnormalities affecting this region, raising doubt over the importance of these proteins in human malignancies. Hemizygous deletions and rearrangements of chromosome 9, band p21, are among the most frequent cytogenetic abnormalities detected in pediatric acute lymphoblastic leukemia (ALL), occurring in approximately 10% of cases. To determine if the p16INK4a/p15INK4b locus might be the target of these chromosomal 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 reaction. Deletions of p16INK4a/p15INK4b were identified in 18 of 20 cases with cytogenetically observed abnormalities of 9p and 5 of 23 with apparently normal chromosomes 9p, with the majority containing bi-allelic deletions (16 homozygous/7 hemizygous). Although most homozygous deletions involved both genes, Southern blot analysis showed an interstitial deletion in a single case that was confined to p16INK4a, suggesting that p15INK4b was not the critical target gene in this case. Sequence analysis of both p16INK4a and p15INK4b in all seven cases with hemizygous deletions failed to show mutations within the coding regions of the retained alleles. In this select group of patients, deletion of p16INK4a/p15INK4b was associated with T-cell phenotype, nonhyperdiploid karyotype (< 50 chromosomes), and poor event-free survival. These findings indicate that deletion of the p16INK4a/p15INK4b 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 kinase inhibitors is important in leukemogenesis.

In vitro drug resistance and prognostic impact of p16INK4A/P15INK4B deletions in childhood T‐cell acute lymphoblastic leukaemia

“…The frequency of p16 deletions in this study, 68´4%, is in agreement with the published data (Hebert et al, 1994;Fizzotti et al, 1995;Ohnishi et al, 1995;Okuda et al, 1995;Diccianni et al, 1997). The majority of these deletions were homozygous, but 7% had hemizygous deletions, i.e.…”

“…Homozygous deletion of p16 in childhood ALL has been reported to be associated with high-risk features and an unfavourable outcome (Fizzotti et al, 1995;Okuda et al, 1995;Takeuchi et al, 1995;Heyman et al, 1996;Kees et al, 1997;Rubnitz et al, 1997;Zhou et al, 1997). However, most of these studies on the prognostic impact of p16 deletions have been performed on childhood ALL in general and are therefore biased by an overrepresentation of (low-risk) B-lineage ALL in the p16 germ-line group and T-ALL with associated high-risk presenting features in the p16-deleted group.…”

Paediatric lymphoblastic T‐cell leukaemia and lymphoma: one or two diseases?

“…Defective cell cycle surveillance mechanisms are likely to be the major factors leading to deregulated proliferation and chromosomal abnormalities that are associated with leukaemic cells. Alterations of chromosome 9p, which contains the CDKN2A/CDKN2B loci encoding for the cyclin-dependent kinase inhibitors p16 INK4A , p15 INK4B and the alternative reading frame protein of the CDKN2A locus, p14 ARF , were reported earlier for ALL in about 30-70% of the cases, with higher frequency in T-ALL compared to precursor B-ALL (Okuda et al, 1995;Heyman et al, 1997;Rubnitz et al, 1997;Takeuchi et al, 2003). The prognostic significance of CDKN2A deletions has remained inconclusive.…”

Loss of function tp53 mutations do not accelerate the onset of myc‐induced T‐cell acute lymphoblastic leukaemia in the zebrafish

“…Moreover, in the setting of murine spontaneous or radiation-induced lymphomagenesis, the tumour suppressor function of TP53 is entirely dependent on ARF (Christophorou et al, 2006;Efeyan et al, 2006). In human T-cell acute lymphoblastic leukaemia (T-ALL), TP53-dependent tumour suppression is typically disabled via ARF inactivation resulting from homozygous deletions of the CDKN2A locus (encoding both ARF and p16INK4a) (Hebert et al, 1994;Fizzotti et al, 1995;Haidar et al, 1995;Okuda et al, 1995). By contrast, TP53 mutations are very rare in T-ALL clinical samples at initial diagnosis, although they do occur more frequently in heavily treated patients at the time of relapse (Wada et al, 1993;Diccianni et al, 1994;Hsiao et al, 1994).…”