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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3405-3409
Chromosome Band 1p36 Contains a Putative Tumor Suppressor Gene
Important in the Evolution of Chronic Myelocytic Leukemia
By
Naoki Mori,
Roberta Morosetti,
Susanne Spira,
Stephen Lee,
Dina Ben-Yehuda,
Gary Schiller,
Raffaele Landolfi,
Hideaki Mizoguchi, and
H. Phillip Koeffler
From the Departments of Medicine and Clinical Pathology, Cedars-Sinai
Medical Center, UCLA School of Medicine, Los Angeles, CA; the
Hemostasis Research Center, Catholic University of Rome, Rome, Italy;
the Department of Hematology, Hadassah Medical Organization, Jerusalem,
Israel; the Department of Medicine, UCLA School of Medicine, Los
Angeles, CA; and the Department of Hematology, Tokyo Women's Medical
College, Tokyo, Japan.
 |
ABSTRACT |
Chronic myelocytic leukemia (CML) is a common neoplasm of
hematopoietic pluripotent stem cells. Although the evolution from chronic phase to blast crisis (BC) in CML patients is an inevitable clinical feature, little is understood about the mechanisms responsible for the transformation. We have previously performed allelotype analysis in CML BC and have detected frequent loss of heterozygosity (LOH) on the short arm of chromosome 1. To know the common region of
LOH where a putative tumor suppressor gene may reside, deletional mapping was performed using 33 microsatellite markers spanning chromosome 1 in 30 patients with CML BC (21 myeloid and 9 lymphoid). DNA was extracted from slides of bone marrow smears or from bone marrow
mononuclear cells. In each patient, DNA from chronic phase was analyzed
alongside DNA from either their BC or accelerated phase. Allelic loss
on 1p was observed in 14 of the 30 individuals (47%): 10 of the 21 myeloid and 4 of the 9 lymphoid BC cases. Serial cytogenetic
information was available in 10 cases with LOH on 1p; interestingly,
deletions in this region were not detected. Two samples showed LOH at
all informative loci on 1p, whereas the other 12 samples showed LOH on
at least one but not all loci on 1p. The common region of LOH resided
proximal to D1S508 and distal to D1S507 (1p36). Our
results suggest that a tumor suppressor gene that frequently plays an
important role in the evolution to BC resides on 1p36 in CML.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
SEVERAL LINES OF evidence have shown that
inactivation of tumor suppressor genes is intimately associated with
tumorigenesis in a wide variety of human tumors.1 The
two-mutation hypothesis suggested that both alleles of a tumor
suppressor gene are inactivated in tumors.2 In fact, such
inactivation of a tumor suppressor gene has been commonly caused by a
mutation of one allele accompanied by loss of the second allele. To
date, loss of heterozygosity (LOH) has been reported to occur on
various chromosomal regions in diverse tumor types. Furthermore,
several tumor suppressor genes have been identified and characterized
from some of these regions showing frequent LOH in tumors.
Chronic myelocytic leukemia (CML) is a common hematologic neoplasm of
pluripotent hematopoietic stem cells. More than 90% of CML cases show
the characteristic Philadelphia chromosome (Ph), which results in the
fusion of sequences of the ABL gene from chromosome 9 with
sequences of the BCR gene from chromosome 22.3,4 In
the absence of effective therapy, the progression from chronic phase to
blast crisis (BC) in CML patients is an inevitable clinical feature and
results in a fatal process. Abnormalities of the tumor suppressor
genes, such as mutations of the p53 gene, absence of RB
protein, and homozygous deletions of the p16INK4a
gene, have been reported to occur during this process in a subset of
CML cases.5-8 Abnormalities of other tumor suppressor genes may also lead to blastic transformation of CML.
Allelotype analysis is a powerful method to identify the regions that
have LOH.9-11 We have previously performed allelotype analysis in 30 patients with CML BC and have detected frequent LOH at
two loci on the short arm of chromosome 1.12 To define a
common region of allelic loss that may harbor putative tumor suppressor
gene(s), we performed deletional mapping of chromosome arm 1p in CML
BC.
| |
MATERIALS AND METHODS |
Samples.
Paired bone marrow samples of chronic phase and either BC or
accelerated phase (AP) were obtained from each patient with CML. Clinical information was available for all 30 patients as shown in
Table 1. Seventeen patients were male and
13 patients were female. Twenty-one patients had myeloid crisis and 9 had lymphoid crisis. Twenty-six BC and 4 AP samples were obtained from
the 30 patients. The mean percentage of blasts for the BC or AP samples was 54.4% (range, 10% to 90%). Cytogenetic data were available for
29 patients.
Extraction of DNA.
DNA was extracted from slides of bone marrow smears derived from each
patient. Cells were stripped off slides with disposable scalpels,
washed once with xylene, washed twice with absolute ethanol, and were
lysed with 50 mmol/L Tris-HCL (pH 8.5), 1 mmol/L EDTA, 0.5% Tween 20, and proteinase K in a final concentration of 100 µg/mL at 37°C
overnight. DNA was extracted twice with phenol and once with
chloroform, and was precipitated in ethanol. The DNA pellets were
dissolved in 40 µL of TE (10 mmol/L Tris-HCL pH 7.4, 1 mmol/L EDTA).
DNA was extracted from bone marrow mononuclear cells from 7 patients
after obtaining their informed consent (CML nos. 5 through 7, CML nos.
23 through 26).13
LOH analysis.
Polymerase chain reaction (PCR)-amplification of microsatellite
sequences was used to determine LOH. Primers for microsatellite sequences were obtained from Research Genetics (Huntsville,
AL).14,15 Each PCR reaction contained 10 ng of DNA, 5 pmole
of each primer, 1 nmole of each dNTP (Pharmacia, Stockholm, Sweden),
0.3 U of Taq DNA polymerase (GIBCO-BRL, Gaithersburg, MD), 2 µCi of
[ -32P]dCTP (ICN, Irvine, CA) in 10 µL of the
specified buffer with 1.5 mmol/L MgCl2. Thirty-two cycles
of denaturing for 40 seconds at 94°C, annealing for 30 seconds at
55°C, and extending for 35 seconds at 72°C were performed in a
Programmable Thermal Controller (MJ Research Inc, Watertown, MA). After
amplification, PCR samples were diluted in the loading buffer
containing 20 mmol/L EDTA, 96% formamide, 0.05% of both bromophenol
blue and xylene cyanol. The products were heated to 94°C for 5 minutes and chilled on ice. Three microliters of the dilutions was
applied to a 5% to 6% polyacrylamide gel containing 8.3 mol/L urea
and separated for 2 to 3 hours at 75 Watts. The gel was
dried and subjected to autoradiography using Kodak
(Eastman Kodak Company, Rochester, NY) XAR film at either
room temperature or  80°C. LOH was scored in informative
cases if a significant reduction ( 50%) in the signal of
the allele from the BC or AP sample was visually noted in comparison to
the corresponding allele from the chronic phase of the same individual.
Where necessary, LOH was assessed by densitometry. In most samples
showing LOH, PCR amplification and analysis were repeated to assure
consistency. For several markers that showed frequent homozygosity in
chronic-phase samples, we performed duplex semiquantitative PCR with
the markers on 1p and markers from chromosome arms other than 1p.
| |
RESULTS |
We screened 30 paired CML samples for LOH with a panel of 33 highly
informative microsatellite markers spanning chromosome 1. Thirty
markers were located on 1p and 3 were on 1q. Each sample was analyzed
at every marker. Some samples were not informative at several loci
because of a shortage of DNA. All patients were informative at multiple
loci on chromosome arm 1p. We performed duplex semiquantitative PCR at
several loci that showed frequent homozygosity in chronic phase
samples, and we did not find occult hemizygosity. Allelic loss on 1p
was observed in 14 of the 30 cases of BC or AP (47%). The most
frequent LOH (8 of 15 informative cases; 53%) was observed at the
D1S468 locus on chromosome band 1p36.
Figure 1 shows examples of allelic loss.
The lower allele was deleted at the D1S468 locus in CML no. 11 (Fig 1A). Heterozygosity was retained at D1S243 and
D1S199. In Fig 1B, LOH was observed at D1S228, whereas
heterozygosity was retained at D1S243 and D1S507 (CML
no. 24). LOH was detected at D1S2667, whereas heterozygosity was retained at D1S508 and D1S199 (Fig 1C, CML no. 1).
No instability was observed in this study.
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| Fig 1.
Loss of heterozygosity on chromosome arm 1p in CML. (A)
LOH was detected on D1S468 in CML no. 11. Heterozygosity was
retained at D1S243 and D1S199. (B) Allelic loss was
observed at D1S228, whereas heterozygosity was retained at
D1S243 and D1S507 (CML no. 24). (C) LOH was found at
D1S2667, whereas heterozygosity was retained at D1S508
and D1S199 (CML no. 1). The locus symbol is shown on the
top. Arrow indicates allele lost. B, blast crisis; C, chronic phase.
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Two of the 14 cases showed LOH at all informative loci on chromosome
arm 1p. Twelve cases showed LOH on at least one marker on 1p but not at
some other markers on this arm. Figure 2
shows the deletional map on chromosome 1 in the 14 cases of LOH. CML no. 1 showed allelic loss at D1S2667 and D1S2672, and
showed retention of heterozygosity at D1S508 and
D1S436. For CML no. 24, LOH was detected at D1S450 and
D1S228, and retention of heterozygosity was observed at
D1S2663 and D1S507. The consensus region of allelic loss was determined to reside proximal to D1S508 and distal to D1S507 (1p36). This region is estimated to encompass 19 centimorgans (cM) of genetic distance.
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| Fig 2.
Deletional map of chromosome 1 in CML. The common region
of LOH was located proximal to D1S508 and distal to
D1S507. Vertical bar indicates the common region of LOH. The
locus symbols are shown on the left. Three loci are located on 1q
(D1S196, D1S215, and D1S202). The sample name
is on the top. Black box indicates LOH. White box indicates retained
heterozygosity. Hatched box denotes not informative.
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Cytogenetic information of BC as well as chronic phase was available
for 10 of the 14 cases with LOH on 1p; however, deletions on 1p were
not detected (Table 1). Clinical information was available for all 30 patients (Table 1). Allelic loss on 1p was observed in both myeloid (10 out of 21; 48%) and lymphoid (4 out of 9; 44%) BC.
| |
DISCUSSION |
The molecular genetic changes of CML have been well studied in the
chronic phase. In contrast, little is known about the mechanisms responsible for BC. To understand the role of genetic changes in the
evolution of CML, we performed deletional mapping of chromosome 1 using
highly informative microsatellite markers. Frequent allelic loss was
observed on chromosome arm 1p in 14 of the 30 cases of BC (47%).
The common region of allelic loss resided proximal to D1S508
and distal to D1S507 (1p36). Frequent LOH has been reported in the same region in several types of tumors, such as neuroblastoma, colorectal, breast and hepatocellular carcinomas, parathyroid adenoma,
and melanoma.16-21 Allelic loss of 1p was associated with unfavorable outcome in neuroblastoma.22 The common region
of allelic loss in the present study partly overlapped with common regions of LOH in these solid tumors.23 However, to date no altered tumor suppressor gene responsible for these tumors has been
identified on chromosome region 1p36. Cloning of candidate gene(s) will
define whether either a single or multiple tumor suppressor genes are
clustered on 1p and are commonly involved in these types of
tumors.
The p18INK4c gene is located on 1p32 and it is
regarded as a tumor suppressor gene.24 Homozygous deletions
of the p16INK4a gene, which is a homolog of the
p18INK4c gene, were reported in lymphoid
BC of CML.6 While the common region of LOH in the
present study was more distal (1p36), 9 of the 14 samples also
showed LOH in the region, including the p18INK4c
gene locus. Therefore, we looked for mutations of the
p18INK4c gene by PCR-SSCP analysis; however, no
mobility shifts were detected in the 30 cases (data not shown). The
p18INK4c gene may not be affected in the
transformation of CML. However, we cannot rule out the
possibility that homozygous deletions of the gene had occurred, because
we were unable to analyze these samples for the gene by Southern blot
analysis.
Recently the p73 gene was identified, and it maps to
1p36.25 The gene is one of the candidates for tumor
suppressor gene on 1p in neuroblastoma. However, the p73 locus
is more distal to the D1S508 locus, and no p73 mutations were
detected in neuroblastoma.25 In addition, although we
screened p73 mutations in various kinds of cell lines and fresh
samples, no mutations were observed (unpublished data). Analysis of the
expression will be helpful to understand the role of the p73
gene in CML.
In 23 of the 30 samples, DNA was extracted from bone marrow smears and
it probably contained both blast and chronic phase cells. Although LOH
was found in a sample of a bone marrow aspirate containing 21% blast
cells (CML no. 8), we may have underestimated the true incidence of
LOH. Similarly, we may have missed homozygous deletions because of the
possible contamination of chronic-phase cells in our BC or AP samples.
Homozygous deletions for a polymorphic marker may appear as retention
of heterozygosity as a consequence of amplification of DNA from the
contaminating chronic phase cells.
Ph has been observed in more than 90% of CML cases. However,
chromosomal deletions or monosomy of chromosome 1 has not been characterized in CML.4,8,26,27 In our study, cytogenetic data were available from 29 patients. Because cytogenetic analysis did
not show either 1p deletions or monosomy of chromosome 1 in any of the
cases with LOH on 1p, our findings suggest that either mitotic
nondisjunction with duplication or mitotic recombination is the
frequent mechanism that resulted in LOH on 1p. The observation that
heterozygosity was retained on 1q in 11 of 12 informative samples with
LOH on 1p suggests that mitotic recombination is the most frequent
mechanism of alteration. Small cytogenetically undetectable deletions
may be present in some of the samples showing LOH on 1p. Nevertheless
except for CML nos. 1, 11, and 24, the LOH covered such a large region
that a deletion would have been detectable cytogenetically.
Cloning and characterization of the affected gene from chromosome arm
1p in progressive CML will help clarify the genesis of blastic
transformation and provide insights into novel therapies.
| |
FOOTNOTES |
Submitted March 25, 1998;
accepted June 26, 1998.
Supported in part by grants from the National Institutes of Health and
the Parker Hughes Fund. H.P.K. is a member of the Jonsson Comprehensive
Cancer Center and holds the Mark Goodson Chair in Oncology Research.
Address reprint requests to Naoki Mori, MD, Department of Medicine,
Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA
School of Medicine, 8700 Beverly Blvd, B208, Los Angeles, CA 90048.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We thank Dr M. Okada (Chromosome Laboratory, Shiseikai Dai-ni Hospital,
Japan) for the help with analysis of the karyotypes.
| |
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Abstract
Introduction
Abstract