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Frequent deletion of p16INK4a/MTS1 and p15INK4b/MTS2 in pediatric acute
lymphoblastic leukemia
T Okuda, SA Shurtleff, MB Valentine, SC Raimondi, DR Head, F Behm, AM Curcio- Brint, Q Liu, CH Pui and CJ Sherr
Department of Pathology, St Jude Children's Research Hospital, Memphis, TN,
USA.
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.
Volume 85,
Issue 9,
pp. 2321-2330,
05/01/1995
Copyright © 1995 by The American Society of Hematology
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