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Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2380-2385
Acquisition of p16INK4A and
p15INK4B Gene Abnormalities Between Initial
Diagnosis and Relapse in Children With Acute Lymphoblastic Leukemia
Kelly W. Maloney,
Loris McGavran,
Lorrie F. Odom, and
Stephen P. Hunger
From the Section of Pediatric Hematology/Oncology, Department of
Pediatrics, and Department of Pathology, University of Colorado School
of Medicine; and The Children's Hospital and the University of
Colorado Cancer Center, Denver, CO.
Although numerous somatic mutations that contribute to the
pathogenesis of childhood acute lymphoblastic leukemia (ALL) have been
identified, no specific cytogenetic or molecular abnormalities are
known to be consistently associated with relapse. The
p16INK4A (p16), which encodes for both
p16INK4A and p19ARF proteins, and
p15INK4B (p15) genes are inactivated by
homozygous deletion and/or p15 promoter hypermethylation in a
significant proportion of cases of childhood ALL at the time of initial
diagnosis. To determine whether alterations in these genes play a role
in disease progression, we analyzed a panel of 18 matched specimen
pairs collected from children with ALL at the time of initial diagnosis
and first bone marrow relapse for homozygous p16 and/or
p15 deletions or p15 promoter hypermethylation. Four
sample pairs contained homozygous p16 and p15 deletions
at both diagnosis and relapse. Among the 14 pairs that were
p16/p15 germline at diagnosis, three ALLs developed homozygous deletions of both p16 and p15, and two
developed homozygous p16 deletions and retained p15
germline status at relapse. In two patients, p15 promoter
hypermethylation developed in the interval between initial diagnosis
and relapse. In total, homozygous p16 deletions were present in
nine of 18 cases, homozygous p15 deletions in seven of 18 cases, and p15 promoter hypermethylation in two of eight cases
at relapse. These findings indicate that loss of function of proteins
encoded by p16 and/or p15 plays an important role in
the biology of relapsed childhood ALL, and is associated with disease
progression in a subset of cases.
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