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 Previous Article | Table of Contents | Next Article 
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
By
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.
 |
ABSTRACT |
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.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
RELAPSED ACUTE lymphoblastic leukemia
(ALL) is the fourth most common malignancy that occurs in
children.1 While approximately 75% of children with newly
diagnosed ALL are expected to be cured with contemporary treatment
regimens, the outcome for children who experience a bone marrow relapse
is poor, with a 6-year survival rate of 20% in a recent report from
the Children's Cancer Group.1 An important challenge is to
define the biologic and genetic basis for these differences in
treatment outcome.
Despite identification of a wide variety of oncogenes and
tumor-suppressor genes (TSGs) that encode for proteins involved in
leukemogenesis, relatively little is known about the genetic features
of relapsed ALL. While it is likely that mutations in genes that encode
proteins involved in transport or metabolism of chemotherapy agents
(eg, MDR1) play a role in the progression of ALL, several
observations indicate that mutations must also develop in specific
oncogenes/TSGs. Relapsed ALL is often sensitive to the same drugs with
which the patient was initially treated, arguing against selection for
absolute drug resistance as a sole explanation for relapse. Permanent
cell lines can be established more frequently from patients at relapse
than at initial diagnosis.2 Similarly, relapse ALL cells
engraft in irradiated immunodeficient mice more readily than cells from
diagnosis.3 Confirming the multihit model of oncogenesis,
oncogene and TSG mutations have been linked to progression in specific
subtypes of leukemia.4-8
Cytogenetic and molecular data suggest that TSG inactivation plays an
important role in leukemogenesis; these same TSGs are also attractive
candidates for the genes involved in progression of leukemia. To date,
p16INK4A (p16, MTSI, CDKN2)
and p15INK4B (p15, MTS2,
CDKN2B) are the only TSGs identified that are inactivated in a
significant percentage of leukemias at the time of initial diagnosis.9,10 p16 and p15, located within
25 kb of one another on the short arm of chromosome 9 (9p21), encode
proteins (p16 and p15) that function as inhibitors of the
cyclin-dependent kinases CDK4 and CDK6, which, complexed with cyclin D,
phosphorylate the retinoblastoma protein (Rb) to allow progression
through the cell cycle.11-13 p16 also encodes a
second protein, p19ARF, via an alternative first exon and
translation of common exons 2 and 3 in a different reading
frame.14 Recent evidence suggests that p19ARF,
which shares no amino acid homology with p16, enhances the functional activity of wild-type p53.15-17 Thus, homozygous
p16 deletion is predicted to functionally inactivate
growth-inhibitory proteins that act upstream of pathways involving both
Rb and p53.18 Animal models support a critical role for
proteins encoded by p16 in oncogenesis, as knockout mice that
lack both p16 and p19ARF, or p19ARF alone,
develop tumors, the most common of which are lymphomas, at greatly
increased frequency.18,19 However, it remains uncertain whether inactivation of p16, p19ARF, or both is the
critical event in human leukemogenesis.
Homozygous deletion of both p16 and p15 occurs in at
least 60% of T- and 20% of B-lineage cases, and is the major means of functional inactivation of the proteins encoded by these genes in
childhood ALL.20-22 In contrast to other tumors,
p16 and p15 point mutations are rarely detected in
childhood ALL.21 p15 is also frequently inactivated
by promoter hypermethylation in T-ALL, but p16 promoter
methylation is uncommon in childhood ALL.22 Limited
information is available regarding potential changes in p16/p15 gene status in the interval between diagnosis
and relapse in childhood ALL. However, p16/p15 lesions
have been associated with progression of other hematolymphoid
malignancies, including chronic myelogenous leukemia (CML) in lymphoid
blast crisis, high-grade and transformed non-Hodgkin's lymphomas, and
myelodysplastic syndromes.7,8,23,24
In this study, we analyzed a panel of 18 matched specimens obtained at
diagnosis and first bone marrow relapse from children with ALL. We
found that homozygous p16/p15 deletions and p15
promoter hypermethylation are frequently acquired in the interval
between initial diagnosis and relapse, suggesting that loss of function of the proteins encoded by these genes may play an important role in
progression of childhood ALL.
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MATERIALS AND METHODS |
Specimens.
Eighteen matched diagnosis and relapse bone marrow samples from
children diagnosed with ALL were available from the cell bank of The
Children's Hospital in Denver. Diagnosis specimens were collected from
1982 to 1994, and relapse specimens were collected from 1982 to 1997. Mononuclear cells were collected by density centrifugation of fresh
bone marrow aspirates, resuspended in 10% dimethyl sulfoxide (DMSO)
and 20% fetal bovine serum, and maintained at either  70°C
or in the vapor phase of liquid nitrogen. In the current study, we
analyzed all matched diagnosis/first bone marrow relapse specimen pairs
collected from patients with greater than 75% blasts in their bone
marrow from whom sufficient material was available that we anticipated
being able to isolate at least 10 µg of DNA. Immunophenotyping was
performed at the time of presentation using panels of monoclonal
antibodies that changed significantly between 1982 and 1997. In
general, sufficient data were available to characterize leukemias as B
or T lineage. All specimens were collected as part of protocols that
had been approved by the Institutional Review Board (IRB) of the
University of Colorado Health Sciences Center (UCHSC) and The
Children's Hospital, and the current retrospective analyses were also
approved by the IRB.
Cytogenetics.
Giemsa-banded cytogenetic studies were performed from unstimulated
cultures of bone marrow aspirate obtained at diagnosis or relapse. From
1982 to 1986, overnight cultures were synchronized using methodology
described by Morse et al.25 After 1986, samples were
prepared using a direct technique and overnight culture methods described previously with and without giant cell tumor supernatant supplementation.26,27 All cytogenetic results were reviewed by one of the authors (L.M.) and, whenever possible, described using
the International System for Cytogenetic Nomenclature (ISCN, 1995).28
Molecular analyses.
Genomic DNA was isolated by standard phenol/chloroform extraction.
Southern blot analysis was performed as described
previously.29 Briefly, membranes containing
BamHI-digested DNAs were cohybridized with a 360-bp DNA
fragment corresponding to p16 exon 2 and a previously described
MLL cDNA probe.30 This p16 probe
cross-hybridizes with p15, allowing detection of deletions of
either p16 or p15. Samples in which p16 and/or
p15 bands were absent or were less than 10% to 20% of the
intensities of control MLL bands were scored as containing
homozygous deletions of the corresponding gene. For leukemias
containing MLL translocations, blots were stripped and
rehybridized with the p16 probe (along with a BCR cDNA
probe) to insure that bands of altered migration did not represent
p16/p15 rearrangements.
To determine the methylation status of the p15 promoter region,
membranes containing HindIII and EagI in combination
with HindIII-digested DNAs were hybridized with a 270-bp
p15 exon 1 probe as previously described.31
Appropriate positive (DNA from the Kg1A cell line, which contains a
hypermethylated p15 promoter) and negative (DNA from a healthy
individual) controls were included on each blot.
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RESULTS |
Characteristics of study population.
We analyzed a panel of 18 paired specimens collected from children with
ALL at initial diagnosis and first bone marrow relapse (Table
1). Relapses occurred at a median of 36.7 months (range, 13 to 82) following initial diagnosis. Seven patients
were classified as B lineage (CD10+, CD19+),
three patients as T lineage (CD7+, CD2+), six
patients were CD10+ but not further phenotyped, and there
were two cases of CD10negative infant ALL. No major
differences in immunophenotype developed in the interval between
initial diagnosis and relapse.
Cytogenetic analyses.
Clonal karyotypic abnormalities were identified in 15 cases at initial
diagnosis. Six ALLs were hyperdiploid with modal chromosome numbers of
52 to 60. Several cases contained recognized, nonrandom cytogenetic
abnormalities, including del(6q) (DR-3, DR-9, DR-14), and t(4;11)
(DR-16). At relapse, the clone observed at initial diagnosis was
observed in eight of 15 cases. Additional numerical and structural
changes were present within this clone in several cases. Of note, a
del(9)(p22p24) developed in the interval between diagnosis and relapse
in case DR-3. Two of 18 cases had incomplete analyses at relapse, and
four of 18 had a 46,XX or 46,XY karyotype at relapse. Clonal
abnormalities were observed at relapse in two of three cases that did
not have clonal abnormalities detected at initial diagnosis.
Cytogenetic analyses were unsuccessful due to culture failure for case
DR-7 at initial diagnosis, but a t(2;11)(p1?12;q23) was identified at
relapse. This translocation did not affect the 11q23 gene MLL,
which was germline at both diagnosis and relapse (data not shown).
Cytogenetic results were not available from DR-20 at initial diagnosis,
when she was 2 months old. At relapse, a t(11;19)(q23;p13) was
observed. Identical MLL rearrangements were present in both the
diagnosis and relapse samples (data not shown), indicating that the
t(11;19) was also present at initial diagnosis.
p16 and p15 gene deletions.
Southern blot analysis was used to determine p16 and
p15 gene status (Fig 1 and Table
1). Four sample pairs contained homozygous p16 and p15
deletions at both diagnosis and relapse. Two of these patients had
T-ALL, and the other two were classified as CD10+ ALLs.
Among the 14 patients who were p16/p15 germline at
diagnosis, three B-lineage ALLs exhibited homozygous deletions of both
p16 and p15 at relapse. In two additional patients
(DR-10, a T-ALL, and DR-18, a CD10+ ALL), homozygous
deletion of p16 was present in the relapse specimens, while
p15 retained germline status. In total, homozygous p16
deletions were present in nine of 18 cases and homozygous p15
deletions in seven of 18 cases at relapse.
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| Fig 1.
p16/p15 deletions in matched diagnostic
and relapse ALL specimen pairs. Autoradiogram of a blot containing
BamH1-digested DNAs cohybridized with p16 and MLL
cDNA probes. The locations of the germline p16,
p15, and MLL bands are indicated by arrows at right.
The migration of molecular size markers are shown in kilobases on the
left. Samples include DNA from dilutions of the K562 cell line, which
has homozygous p16 and p15 deletions, into normal DNA
to simulate deletions in 50% and 10% of the cell population; a
healthy control (NORM); K562; and four matched diagnostic (Dx) and
relapse (R) patient samples (no. 4, 10, 17, 6). The gene status of
p16 and p15 is listed above each patient sample (G,
germline; D, deleted). Faint residual p16 and p15 bands
(<10%) in no. 6 relapse patient sample are due to contamination with
small amounts of normal cells.
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p15 promoter hypermethylation.
Using the strategy outlined in Fig 2, we
determined whether or not the p15 promoter region was
hypermethylated, which correlates with silencing of gene expression, in
samples that did not contain p15 deletions. Sufficient DNA was
available to perform these analyses for eight diagnostic samples.
p15 exon 1 was homozygously hypermethylated in three of these
eight patients, and unmethylated in the remaining five (Table 1).
Sufficient DNA was available to perform these analyses for eight of 11 p15-germline relapse specimens. Two cases reproducibly showed
partial p15 promoter hypermethylation (Fig 2 and Table 1),
suggesting either that one allele was hypermethylated in all cells, or
that a subpopulation, accounting for about half the cells, was
homozygously hypermethylated. We observed several different patterns of
p15 methylation status in the matched specimens. Particularly
interesting is case DR-10, which had no evident p16/p15 abnormalities at initial diagnosis, and contained homozygous
p16 deletion and heterozygous p15 promoter
hypermethylation at relapse (Figs 1 and 2).
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| Fig 2.
p15 promoter hypermethylation. (A) Schematic
representation of p15 exon 1 and surrounding HindIII
(H3) and EagI (E) sites. The p15 probe used (indicated
above) hybridizes to exon 1. A 2.8-kb band is seen when the samples are
digested with HindIII alone. When the samples are digested with
EagI (a methylation-sensitive enzyme) in combination with
HindIII, a 0.6-kb band is recognized by the probe if the gene
is unmethylated (cuts at EagI) and a 2.8-kb band is present if the
sample is methylated (does not cut at EagI) (note that a 2.2-kb
band is not seen, because the exon 1 probe does not hybridize to this
region of DNA). (B) Autoradiogram of a blot containing HindIII
and EagI-in combination with HindIII-digested DNAs
hybridized with the p15 exon 1 probe. The locations of the
expected 2.8-kb and 0.6-kb bands are indicated by arrows at the left.
Samples include DNA from Kg1A cell line, a healthy control (NORM),
DR#10 at diagnosis (Dx) and at relapse (R). Homozygous methylation is
seen in Kg1A, and hemizygous methylation in DR#10 at relapse, but not
at initial diagnosis.
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DISCUSSION |
In the current study, we found that homozygous p16 deletions
were common at the time of first bone marrow relapse of childhood ALL
(9 of 18 cases). While four of these cases contained homozygous deletions at both diagnosis and relapse, 5 of the 14 cases (36%) that
were p16/p15 germline at diagnosis acquired homozygous
p16 deletions in the interval between diagnosis and relapse.
Three of these five cases also acquired homozygous p15
deletions, and one acquired a partial p15 exon 1 hypermethylation. One additional case acquired partial p15
promoter hypermethylation at relapse in the absence of p16
abnormalities. These results suggest that acquisition of p16
and p15 abnormalities may be a critical event associated with
disease progression in children with ALL. As all deletions involved
p16 exon 2, which is included in both p16 and p19ARF transcripts,14,19 it is not
certain whether the critical protein target was p16,
p19ARF, or both. Experimental data indicate that
inactivation of these two proteins profoundly alters cell-cycle
progression and growth arrest via loss of a negative regulator of the
Rb pathway (p16) and a positive regulator of wild-type p53 activity
(p19ARF),11-13,15-17 suggesting that these
alterations may contribute to the clinical chemotherapy refractoriness
observed in relapsed ALL.
It is important to emphasize that our results do not distinguish
between two different potential explanations for the presence of
p16/p15 abnormalities in relapse, but not diagnosis,
samples. First, the p16/p15 abnormalities may not have
been present in any of the leukemic cells at diagnosis, but rather
developed during (and perhaps instigated) the process of disease
recurrence. Alternatively, a small subclone, that was below the limits
of detection of Southern blot analysis, containing these genetic
abnormalities could have been present at the time of initial diagnosis,
and loss of p16/p15/p19ARF function could have conferred a
proliferative and/or survival advantage that allowed this to become the
dominant clone at relapse.
To our knowledge, this is the largest series of childhood ALLs in which
p16 and p15 gene status has been determined in matched diagnostic and relapse specimen pairs. Ohnishi et al reported that
p16 status was unchanged (one deleted, six germline) between diagnosis and relapse in seven paired samples.21 Takeuchi
et al used microsatellite analysis to identify deletions within 9p in
six matched pairs of childhood ALLs and found that no differences developed in the pattern of allelic loss between diagnosis and relapse.32 In contrast, Ogawa et al found that at least
hemizygous loss of p16 developed between initial diagnosis and
relapse in two of three paired samples.33 To determine
whether there is any cytogenetic data to support our findings that
acquisition of p16/p15 abnormalities are likely to play
an important role in progression of childhood ALL, we reviewed the
published literature on karyotypes from children with relapsed ALL,
focusing on 9p abnormalities. In five series, complete karyotypes were
available from 34 cases of childhood ALL that had an abnormal karyotype at diagnosis, and had additional changes within this clone at relapse.34-38 Deletions of 9p evolved between diagnosis and
relapse in four of these 34 (12%) cases. As the majority of ALLs
containing p16/p15 deletions do not have visible 9p
abnormalities (and only one of the five cases that acquired
p16/p15 deletions in our study also acquired visible 9p
abnormalities), these cytogenetic data likely underestimate the true
incidence of new p16/p15 abnormalities.
Taken together with data from other studies,7,8,23,24,39
these results strongly suggest that p16/p15 genetic
abnormalities play an important role in the biology of relapsed
hematologic and lymphoid malignancies, and may be directly related to
disease progression. Our sample is too small, and the clinical
characteristics and treatment of the patients too heterogeneous, to
draw any conclusions regarding the potential prognostic import of
p16/p15 abnormalities at relapse. In the future, it
will be important to analyze a larger, more homogeneous group of
patients to accurately define the percentage of childhood ALLs that
acquire p16/p15 abnormalities in the interval between
initial diagnosis and relapse, and to determine whether this has
prognostic significance. Increased understanding of the role of
p16/p15 inactivation in the initiation and progression of lymphoid malignancies should provide important insights into leukemia biology and lay the groundwork for rationally designed therapeutic interventions.
| |
FOOTNOTES |
Submitted June 18, 1998; accepted November 25, 1998.
K.W.M. is the recipient of the Greg and Laura Norman Fellowship Award
from the National Childhood Cancer Foundation and is also supported in
part by a University of Colorado Cancer Center seed grant. S.P.H. was
supported by a BLOOD/ASH Scholar Award and a Professional Development
Award from The Children's Hospital Research Institute, Denver, CO, and
is a Leukemia Society Translational Research Awardee. Research
supported by a grant from the Cancer League of Colorado to S.P.H. and a
Cancer Center Core Grant (CA 46934).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Stephen P. Hunger, MD,
UCHSC Campus Box C229, 4200 E Ninth Ave, Denver, CO 80262; e-mail:
Stephen.Hunger{at}UCHSC.edu.
| |
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ABSTRACT
INTRODUCTION