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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4031-4035
RAPID COMMUNICATION
Molecular Cytogenetic Characterization of a Critical Region in Bands
7q35-q36 Commonly Deleted in Malignant Myeloid Disorders
By
Konstanze Döhner,
Jill Brown,
Ute Hehmann,
Claudia Hetzel,
Janet Stewart,
Gordon Lowther,
Claudia Scholl,
Stefan Fröhling,
Antonio Cuneo,
Lap C. Tsui,
Peter Lichter,
Stephen W. Scherer, and
Hartmut Döhner
From Medizinische Klinik and Poliklinik V, University of Heidelberg,
Heidelberg, Germany; Duncan Guthrie Institute of Medical Genetics,
Glasgow, UK; Dipartimento di Scienze Biomediche e Terapie Avanzate
Universita Degli Studi di Ferrara, Ferrara, Italy; the
Department of Genetics, The Hospital for Sick Children, Toronto,
Ontario, Canada; and Abteilung "Organisation komplexer Genome,"
Deutsches Krebsforschungszentrum, Heidelberg, Germany.
 |
ABSTRACT |
Loss of chromosome 7 ( 7) or deletion of the long arm (7q) are
recurring chromosome abnormalities in myeloid leukemias. The association of 7/7q with myeloid leukemia suggests that these regions contain novel tumor suppressor gene(s), whose loss of function
contribute to leukemic transformation or tumor progression. Based on
chromosome banding analysis, two critical regions have been identified,
one in band q22 and another in bands q32-q35. Presently there are no
data available on the molecular delineation of the distal critical
region. In this study we analyzed bone marrow and blood samples from 13 patients with myeloid leukemia (de novo myelodysplastic syndrome
[MDS] , n = 3; de novo acute myeloid leukemia [AML], n = 9;
therapy-related (t-) AML, n = 1) which, on chromosome banding
analysis, exhibited deletions (n = 12) or in one case a balanced
translocation involving bands 7q31-qter using fluorescence in situ
hybridization (FISH). As probes we used representative clones from a
contig map of yeast artificial chromosome (YAC) clones that spans
chromosome bands 7q31.1-qter. In the 12 cases with loss of 7q material,
we identified a commonly deleted region of approximately 4 to 5 megabasepairs in size encompassing the distal part of 7q35 and the
proximal part of 7q36. Furthermore, the breakpoint of the reciprocal
translocation from the patient with t-AML was localized to a 1,300-kb
sized YAC clone that maps to the proximal boundary of the commonly
deleted region. Interestingly, in this case both homologs of chromosome 7 were affected: one was lost (7) and the second exhibited the t(7q35). The identification and delineation of translocation and deletion breakpoints provides the first step toward the identification of the gene(s) involved in the pathogenesis of 7q35-q36 aberrations in
myeloid disorders.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
CHROMOSOME 7 has been a focus of
attention as a site harboring tumor suppressor genes since cytogenetic
studies have shown deletions of its long arm (7q) in various tumor
types.1,2 In myeloid disorders, loss of chromosome 7 (7) or deletion of the long arm (7q) are among the most
common recurrent chromosome abnormalities. These aberrations are
associated with myelodysplastic syndrome (MDS) and acute myeloid
leukemia (AML), in particular with therapy-related MDS/AML
(t-MDS/t-AML) following therapy with alkylating agents or secondary
MDS/AML after occupational exposure to chemical
mutagens.3-5 Furthermore, 7/7q occur in MDS
and AML that develop in patients with constitutional disorders (eg, Fanconi's anemia, Kostmann's syndrome, neurofibromatosis type 1, familial monosomy 7).6 Clinically, myeloid leukemias
exhibiting 7/7q have been associated with high
susceptibility to infections, poor response to chemotherapy, and short
survival times.3,7
By chromosome banding analysis two critical regions on the long arm of
chromosome 7 have been identified, one in band 7q22 and another in
bands 7q32-q35.5,8-11 The recurrent loss of genetic material suggests that these regions contain as yet unidentified tumor
suppressor gene(s) which contribute to myeloid leukemogenesis. The
molecular delineation of the proximal critical region in 7q22 has been
the focus of several investigations.11-16 Using
fluorescence in situ hybridization (FISH) and loss of heterozygosity
(LOH) studies, distinct critical regions in bands 7q22-q31.1 have been identified which are shown to be commonly deleted or to contain translocation/inversion breakpoints in myeloid
disorders.11-16
The distal critical region in 7q has so far only been delineated by
chromosome banding analysis. In a study by Rodrigues Pereira Velloso et
al10 of 54 patients with MDS and AML, bands 7q22 and 7q32
were most commonly deleted in the proximal and distal critical region,
respectively. Le Beau et al11 reported on 16 cases with de
novo MDS/AML and t-MDS/t-AML exhibiting deletions involving the distal
part of 7q. All deletions were interstitial with the proximal and the
majority of distal breakpoints localized to 7q31 or 7q32 and 7q36,
respectively. The commonly deleted segment in this study was delineated
to bands 7q32-q33.
In the present study, we analyzed samples from 13 patients with myeloid
leukemia exhibiting deletions or a translocation affecting bands
7q31-qter by FISH. As probes we selected representative yeast
artificial chromosome (YAC) clones from a physical map encompassing bands 7q31-qter.17-19 Because overlapping YACs were used,
it was possible to systematically delineate the extent of the deletions and to locate the breakpoint of one reciprocal translocation at the
molecular level.
| |
MATERIALS AND METHODS |
Patients.
Bone marrow and/or blood samples from 13 patients with myeloid
disorders (de novo MDS, n = 3 [nos. 1-3]; de novo AML, n = 9 [nos.
4-12]; t-AML, n = 1 [no. 13]) were studied which, on chromosome banding analysis and/or FISH, exhibited deletions or
translocations of bands 7q31-qter (Table
1). Chromosome banding analysis was performed using standard methods,
and the karyotypes were designated according to the International
System for Cytogenetic Nomenclature.20
DNA probes.
For the metaphase and interphase FISH experiments, we selected
representative clones from a panel of YAC clones
(Fig 1) that were previously
mapped to chromosome bands 7q31.1 to 7qter (genes which are present on
each YAC are given in parentheses)17-19,21: HSC7E161
(PDS, PRKAR2B, DRA), HSC7E132, HSC7E589,
HSC7E222, HSC7E648, HSC7E1175 (ALDR1, BPGM,
CALD1), HSC7E116 (CHRM2), HSC7E190, HSC7E248 (CLCN1, NEDD2), HSC7E630 (CLCN1,
NEDD2), C_940_a_12 (NEDD2, TRCB, PRSS1,
KEL, PIP1, CLCN1), C_761_H_5 (TIM1),
C_745_G_6, C_945_H_1, HSC7E162, C_932_D_12, HSC7E124, HSC7E131,
C_868_G_5, C_880_B_7, HSC7E113, C_724_G_5 (RHEB), HSC7E802
(XRCC2), HSC7E224, HSC7E769 (DPP6, HTR5A,
APCR), and HSC7E526 (VIPR2). Clones HSC7E248 through HSC7E113 recognize a contiguous genomic fragment in 7q35-q36. Detailed
information on the YACs is available at:
http://www.genet.sickkids.on.ca/chromosome7/ and
http://www.cephb.fr/ceph-genethon-map.html.
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| Fig 1.
Mapping of deletions and a translocation involving
chromosome bands 7q31-qter in 13 myeloid leukemias by FISH. HSC7E-YACs
are from the chromosome 7-specific YAC library17 and the
C_row_plate_ column YACs are from the CEPH-Généthon
collection.21 Clones HSC7E248 to HSC7E113 recognize a
contiguous genomic fragment in chromosome bands 7q35-q36. del, deletion
(only one fluorescence signal); t, translocation breakpoint; di, disomy
(two fluorescence signals indicating retention of both alleles); empty
boxes, not done; light gray boxes, extent of the deletion; dark gray
boxes, commonly deleted segment.
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To ensure that the distal 7q deletions did not contiguously involve the
proximal critical region in 7q22-q31, all cases were also hybridized
with YAC clones HSC7E481 (7q21.1-q21.3) and HSC7E506 (7q22). We
previously showed that YAC HSC7E506 recognizes a genomic fragment that
is contained in the proximal critical region.12
Human sequences from the YAC clones were generated by a polymerase
chain reaction (PCR) protocol using primers directed against Alu-sequences.22 Amplification was performed in a 100-µL
reaction mixture containing approximately 160 ng YAC-DNA, 100 mmol/L of the four dNTPs (Boehringer Mannheim, Mannheim, Germany), 10 µL PCR-buffer (Boehringer Mannheim), and 2.0 mmol/L MgCl2
(Boehringer Mannheim). Three Alu-PCR reactions were performed using
either the primers CL1, CL2, or a combination of both (0.5 µmol/L).
The products of all three reactions were combined for use in the FISH experiments. The Alu-PCR products were labeled by nick translation with
biotin-16-dUTP or digoxigenin-11-dUTP (Boehringer Mannheim).
FISH.
FISH was performed as described.23,24 The hybridization
mixture contained approximately 250 ng labeled Alu-PCR product, 10 µg
Cot-1 DNA fraction (BRL/Life-Technologies, Gaithersburg, MD), and 10 µg salmon sperm DNA (Sigma Deisenhofen, Germany).
Interphase cytogenetic analysis was performed for deletion mapping. To
monitor the hybridization efficiency we cohybridized with a YAC clone
from 7q that mapped outside the region of interest. By analogy to our
previous studies on deletion analyses, the cut-off level was defined by
the mean + 3 SD of the frequency of control cells exhibiting only one
fluorescence signal.12,23 The cut-off levels were
determined for five representative YACs from the YAC map (range, 4.5%
to 7.6%). Signal numbers were enumerated in 200 to 300 nuclei. The
breakpoint of the balanced translocation t(3;7)(p13;q34 or q35) was
additionally identified by metaphase FISH.
| |
RESULTS |
Chromosome banding analysis.
As determined by chromosome banding analysis, 11 of the 13 cases had
aberrations involving bands 7q31-qter. The remaining two cases had
monosomy 7 (no. 4) and a deletion del(7)(q?22) (no. 8) within a complex
karyotype including unidentified marker chromosomes. The loss of 7q
material resulted from terminal deletions (cases 1, 6, 7, 8, and 10)
and unbalanced translocations (cases 2, 3, 5, 9, 11, and 12). The
commonly deleted segment was defined as 7q35-qter (see
Fig 2). Case 13 exhibited a
balanced translocation t(3;7) with a breakpoint in band 7q34 or q35.
Interestingly, this case also had monosomy 7. This patient had received
total body irradiation and high-dose cyclophosphamide followed by
autologous bone marrow transplantation for stage IV follicular
lymphoma. Two years after transplantation the patient developed t-MDS
which rapidly progressed to t-AML. Cytogenetic analysis of
phytohemagglutinin (PHA)-stimulated blood at the time of diagnosis of
the t-AML showed a normal karyotype. The karyotypes of the 13 leukemias
are given in Table 1.
View larger version (17K):
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| Fig 2.
Deletions or translocations involving chromosome bands
7q31-qter in 13 patients with MDS, AML, and t-AML identified by
chromosome banding analysis. The commonly deleted segment is delineated
by the grey area. Line, deletion; point, translocation breakpoint; *,
monosomy 7 within a complex karyotype.
|
|
Deletion and translocation mapping by FISH.
The results of the deletion/translocation mapping by FISH are given
in Fig 1. To delineate the commonly deleted segment in 7q31-qter at
the molecular level, we selected a panel of YACs distributed along
7q31.1-qter, including a set of contiguously mapped YACs in bands
7q35-q36. In the 12 MDS/AML cases exhibiting 7q deletions, unbalanced
7q translocations, or monosomy 7 within a complex karyotype, we
identified a commonly deleted region in bands 7q35-q36. In the case of
t-AML with the t(3;7), we localized the 7q breakpoint to a 1,300-kb
sized genomic segment in 7q35.
The commonly deleted segment in the 12 MDS/AML cases extended from YAC
HSC7E124 in the distal part of band 7q35 to YAC C_724_G_5 in the
proximal part of band 7q36 (Fig 1). This segment comprises approximately 4 to 5 megabasepairs (Mb). The proximal
boundary of this segment was defined by cases 4 and 5. As illustrated
in Fig 1, there is marked heterogeneity of the proximal deletion breakpoints among the cases: within bands 7q31.1-q35 the breakpoints were scattered along a large region extending from the genomic segments
recognized by YAC HSC7E132 (case 3) to YAC HSC7E124 (cases 4 and 5). In
case 12 the proximal deletion breakpoint was located between YAC
HSC7E161 (7q31.1) and YAC HSC7E506 (7q22). For case 6 we could not
determine the exact proximal deletion breakpoint because of the limited
amount of material available. The distal boundary of the commonly
deleted segment was defined by cases 4 and 6. In the remaining cases
the deletions extended distal to the genomic region identified by YAC
C_724_G_5 in band 7q36. In 5 (nos. 2, 5, 9, 11, and 12) of the 12 deletion cases, there was loss of the telomeric sequences (detected by
YAC HSC7E526). Interestingly, case 6 had a noncontiguous deletion
involving a genomic fragment in the proximal critical region in
7q22-q31 (identified by YAC HSC7E506) and in the distal critical region
7q35-q36 (identified by YACs HSC7E124 to C_724_G_5). In contrast to the
interpretation of chromosome banding analysis, bands 7q32-q35 were
retained. None of the other cases had deletion within the proximal
critical region in 7q22-q31.
The breakpoint of the t(3;7)(p13;q34 or q35) (case 13) was mapped to a
1,300-kb genomic segment encompassed by YAC C_945_H_1 in band 7q35.
This genomic fragment is located near the proximal boundary of the
commonly deleted region. Based on the available physical map from this
region, the distance between the translocation breakpoint and the
commonly deleted region is estimated to be in the range of 2 to 3 Mb.
There was no deletion detectable in the homolog involved in the
translocation. FISH using YAC C_945_H_1 and a centromere 7 specific
probe (Oncor Inc, Gaithersburg, MD) confirmed the results from
chromosome banding analysis that the tumor also had monosomy 7. FISH
using the centromere 7 probe and YAC C_945_H_1 on PHA-stimulated blood
from this patient that was obtained at the time of the development of
t-AML showed two hybridization signals for both probes, indicating that
the translocation t(3;7) was not constitutional but somatically
acquired. These data are supported by FISH with the same probes
performed on mononuclear cells from the autologous bone marrow graft
obtained 2 years before the development of t-AML. Hybridization again
showed two fluorescence signals for the centromere 7 probe and YAC
C_945_H_1.
| |
DISCUSSION |
Using FISH with YAC clones of defined physical position, we identified
a commonly deleted genomic segment in 12 cases of myeloid leukemias
exhibiting deletions of the distal part of 7q. Furthermore, we mapped
the translocation breakpoint of a reciprocal translocation to a
1,300-kb sized genomic segment that is located at the proximal boundary
of the commonly deleted region.
In the 12 MDS/AML cases with loss of 7q material we delineated a
commonly deleted genomic segment of approximately 4 to 5 Mb in size
encompassing the terminal part of band 7q35 and the proximal part of
band 7q36. The proximal breakpoints in the deletion cases scattered
along a large region extending from bands 7q31.1 to 7q35. The distal
boundary of all the deletions extended into band 7q36, with 5 of the 12 cases involving the telomeric sequences detected with YAC HSC7E526.
With respect to the chromosomal location of the critical region, our
data are at variance to those obtained by chromosome banding analysis.
In two recent chromosome banding studies, the commonly deleted region
was assigned to bands 7q32-q33, whereas in our study the critical
segment was delineated to a more distal region in
7q35-q36.10,11 FISH using probes from a defined physical
map is the more sensitive technique for the delineation and chromosomal
mapping of a critical segment, particularly in a region where
chromosomal assignment of breakpoints may be difficult. In one of our
cases (no. 6) we were able to identify a noncontiguous deletion by FISH
involving the proximal (7q22-q31) and the distal (7q35-q36) critical
region. Such high resolution cannot be achieved by the chromosome
banding techniques.
In one case of t-AML, the translocation breakpoint of a reciprocal
translocation t(3;7)(p13;q34 or q35) was identified and localized to a
1,300-kb sized genomic segment that is localized near the proximal
boundary of the commonly deleted region. Interestingly, in this case
chromosome 7 was homozygously affected by somatically acquired
rearrangements, one homolog was lost (7), and the second exhibited the t(7q34 or q35). One may speculate that the translocation breakpoint disrupts a gene relevant to the leukemogenic event. Translocations commonly lead to the activation of proto-oncogenes or to
chimeric fusion genes; however, some translocations have been shown to
be accompanied by submicroscopic deletions and have led to the
identification of a genomic segment likely containing a novel tumor
suppressor.25,26 Based on the physical map available, the
estimated distance between the translocation breakpoint and the
commonly deleted region is approximately 2 to 3 Mb. One possible interpretation of the significance of this translocation breakpoint is
that by analogy to the proximal critical region in 7q22-q31there is
heterogeneity of the translocation and deletion
breakpoints.11-13,16 More than one gene in either critical
region of chromosome 7 could be involved.
Only the gene encoding ras homologue enriched in brain 2 (RHEB)
has been mapped to the commonly deleted region.27 The
region has not yet been fully sequenced; thus, it is likely that other unidentified genes localize to this region. None of the genes that are
located in the distal part of 7q and may be candidates based on their
protein function such as NEDD2, XRCC2, and TIM map to
the commonly deleted region or to the genomic segment containing the
translocation breakpoint.28-30
In the present study, we defined a genomic fragment in chromosome bands
7q35-q36 that is commonly affected in malignant myeloid disorders.
Refinement of the critical region by the analysis of additional tumor
samples together with the growing data from the human chromosome 7 mapping and sequencing project will facilitate the identification of
the relevant disease gene(s).
| |
ACKNOWLEDGMENT |
We gratefully acknowledge the members of the German multicenter AML HD
Study Group and Dr B. Mohr for providing leukemia specimens.
| |
FOOTNOTES |
Submitted August 12, 1998;
accepted September 23, 1998.
Supported by the Forschungsförderungsprogramm of the Medical
Faculty, University of Heidelberg, and the Medical Research Council
(MRC) of Canada (to S.W.S. and L.C.T.). S.W.S. is a Scholar of the MRC
and L.C.T. is a Senior Scientist of the MRC.
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 Hartmut Döhner, MD,
Medizinische Klinik and Poliklinik V, University of Heidelberg,
Hospitalstra e 3, 69115 Heidelberg, Germany; e-mail:
hartmut_doehner{at}ukl.uni-heidelberg.de.
| |
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Top
Abstract
Introduction