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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1514-1519
Shortened Telomeres Involved in a Case With a Jumping Translocation at
1q21
By
Shinji Hatakeyama,
Kazuhiro Fujita,
Hiraku Mori,
Mitsuhiro Omine, and
Fuyuki Ishikawa
From the Department of Life Science, Tokyo Institute of Technology,
Yokohama; and the Division of Hematology, Showa University Fujigaoka
Hospital, Yokohama, Japan.
 |
ABSTRACT |
The jumping translocation (JT) is a rare chromosomal abnormality in
which a specific chromosomal segment translocates onto the ends of
various chromosomes (jumps). In most cases, the region distal to 1q21
jumps onto numerous different telomeres. Here we report a molecular
study of the JT involving 1q21 found in a patient with acute
myelomonocytic leukemia that had transformed from myelodysplastic syndrome (MDS). This is the first report describing the analysis of the
molecular structure of the JT. We demonstrated the presence of a
stretch of telomeric repeats at the breakpoint by means of a
fluorescence in situ hybridization experiment, molecular cloning, and
nucleotide sequencing of the fused region. A significant amount of
variant telomeric repeats (a telomeric sequence having one-base mismatch within the authentic telomeric repeat TTAGGG) was found in
this region. The variant telomeric repeat has been shown to be present
in the proximal region of telomeres and does not perform telomeric
functions by itself. Therefore, these results indicated that the
telomeres had already been critically shortened when the jumps
occurred. We suggest that the extended proliferation of cancer cells
during the premalignant stage, such as MDS, results in chromosomal
instability due to the loss of telomeric functions.
| |
INTRODUCTION |
TELOMERES PLAY a critical role in
chromosomal stability.1 In most somatic cells, the telomere
length is shortened each time the cell divides.2 When the
telomere length reaches a critical point, the cells cease to divide
which leads to senescence. However, cancer cells overcome this negative
regulation of cell division induced by the shortened telomeres, and
continue to proliferate.3 The resultant chromosome
instability, caused by the loss of telomeric functions, has been
proposed as a mechanism of cancer cell evolution.4 However,
there has been no report actually implicating this hypothesis in human
clinical cancers. An example of a chromosomal abnormality that
apparently involves the telomere is the jumping translocation (JT).5 JT is an unbalanced translocation of a specific
chromosomal segment onto the ends of various chromosomes (jumps). About
20 cases of JT have been reported in leukemia patients.5-15
In most cases, the donor segments originated from the long arm of
chromosome 1. In contrast, the acceptor telomeres varied greatly among
patients and even within any one patient. These observations suggest
that some general features of telomeres, such as insufficient telomeric function, may have caused JT. However, molecular cloning of the fusion
points has not yet been reported, and thus it was unknown whether jumps
occurred toward the telomeres, subtelomeric regions, or nontelomeric
regions.
Here we report the molecular structure of the JT fusion point. We have
demonstrated the presence of telomeric repeats at the fusion point.
Interestingly, these telomeric repeats consist of so-called variant
telomeric repeats and the authentic TTAGGG telomeric repeats were only
found to a limited degree. Variant telomeric repeats have been reported
to be located at the inner regions of native telomeres and do not
perform telomeric functions in vivo. Therefore, this study suggests
that the excessive proliferation of cancer cells results in the
exposure of the variant telomeric repeats and telomere dysfunction
leading to the chromosomal abnormality of JT.
| |
MATERIALS AND METHODS |
Probes.
The telomeric repeat (TTAGGG)n was generated by
polymerase chain reaction (PCR).16 In brief, a
PCR reaction was performed in a 0.1-mL volume containing 10 pmol of the
primers (TTAGGG)4 and (CCCTAA)4, 2 U of
Taq polymerase, 0.2 mmol/L of each dNTP, and a standard buffer.
Amplification consisted of 10 cycles of 1 minute at 94°C, 30 seconds
at 55°C, and 1 minute at 72°C, followed by 30 cycles of 1 minute at
94°C, 30 seconds at 60°C, 90 seconds at 72°C, and one final step
of 5 minutes at 72°C.
A JT-specific, nontelomeric sequence (probe A) was prepared from the
EcoT14 I clone by EcoT14 I and Bgl I digestion.
The resultant 330 bp was purified from an agarose gel and used as a
probe for Southern blot analysis and for screening of the human genomic library.
Cytogenetic analysis.
Cytogenetic analyses were performed according to standard procedures.
Giemsa-banding was used for routine analysis of metaphase preparations.
A fluorescence in situ hybridization (FISH) experiment was performed
according to standard procedure. In brief, a probe was labeled with
biotin-21-dUTP using a nick translation kit. The slides were denatured
in 70% formamide in 2 × SSC (1 × SSC = 0.15 mol/L NaCl, 0.015 mol/L sodium citrate, pH 7.0) at 75°C for 10 minutes. After
dehydration of the slides, the labeled probe was applied at a
concentration of 0.5 µg/mL in 4 × SSC, 50% formamide, 20% dextran
sulfate with 100 µg/mL herring sperm DNA. The slides were hybridized
overnight at 42°C and then washed at 37°C in 2 × SSC, 50%
formamide for 15 minutes, followed by 2 × SSC, 1 × SSC for 15 minutes.
The biotin-labeled probe was detected using fluorescein avidin and a
biotinylated anti-avidin antibody. Chromosomes were counterstained with
propidium iodide and visualized using a microscope (Zeiss, Thornwood,
NY) with appropriate filters. Metaphase spreads were captured using a
CCD camera system (Photometrics, Tucson, AZ).
Southern blot analysis.
Approximately 10 µg of human genomic DNA was digested with BAL31 in a
standard buffer for 70 minutes (the final concentration was 20 U/mL) at
30°C. After phenol extraction and ethanol precipitation, the
BAL31-digested human genomic DNAs were digested with Hinf I for
6 hours at 37°C. Restriction fragments were separated on a 0.6%
agarose gel run at 20 V for 16 hours in 1× Tris/Borate/EDTA (TBE)
buffer. The gel was then stained with dilute EtBr,
denatured in 0.4 N NaOH for 30 minutes, and the DNAs were transferred
by capillary action onto a Hybond-N+ nylon membrane (Amersham,
Arlington Heights, IL). The blot was rinsed in 20× SSC,
and hybridized at 42°C for 20 hours in 50% formamide, 1% sodium
dodecyl sulfate (SDS), 5× SSC, 5× Denhart's solution, and 10 µg/mL herring sperm DNA against a DNA probe labeled with
[32P] dCTP by nick translation. Filters were then
washed for 10 minutes at room temprature in 0.1× SSC and 0.1% SDS,
dried, wrapped, and exposed to Hyperfilm (Amersham) for 2 to 3 days at  80°C.
Genomic cloning.
Genomic DNAs were digested (Tsp509 I or EcoT14 I),
ligated to an EcoRI linker, size-selected in a low melting
point agarose gel (6 to 9 kb for the JT-specific fragment, or 2 to 3 kb
for a normal allele), purified using  -agarase, and ligated to lambda ZAP II/EcoRI. These subgenomic libraries were screened using
the telomeric repeat or the nontelomeric, JT-specific sequence (probe A). A  phage genomic library was constructed according to standard procedure using the GEM12 half site vector.
| |
RESULTS |
Karyotypes of the jumping translocation.
We studied one leukemia patient showing typical JT karyotype anomalies.
The 55-year-old patient was diagnosed as acute myelomonocytic leukemia
(AMMoL) in June 1994. She was treated by intermittent courses of the
low-dose AraC regimen with minimal response, and died of massive
bleeding in June 1995. Surface marker analysis showed that the leukemic
cells were positive for CD13, CD14, CD33, CD34, and HLA-DR. The
karyotypes and hematological findings of the patient during the
clinical course are shown in Table 1. The
leukemic cells showed a normal karyotype in June 1994, developed a
variety of JTs in September 1994 and March 1995. The basic JT karyotype
involved the donor chromosomal segment distal to 1q21 jumping onto the
tip of the short arm of chromosome 7 [46, XX, der(7)t(1; 7)(q21; p22),
see Table 1 and Fig 1A]. In most cells, an
additional JT involving the same donor segment of 1q jumping onto the
tip of 3q, 4p, 5q, 7p, 8q, 9q, 13q, 21q, or 22q was also present (Fig
1B). These karyotypes resulted in 1q tetrasomy in most cells.
Interestingly, the frequency of the different sets of JTs varied
between September 1994 and March 1995: A particular set of JTs
involving 7p and 5q showed 88% domination of the leukemic population
in March 1995. However, leukemic cells with JTs were taken over by a
clone with a completely different karyotype [46, XX, add(16)(q24)] in
May 1995 (Table 1).
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| Fig 1.
The karyotypes of the jumping translocation. (A) The
normal 1q21-ter (left) and the fused 1q21-ter onto the telomere of 7p (right). (B) Other fused 1q21-ter onto the telomeres of a variety of
chromosomes (3q, 4p, 5q, 7p, 8q, 9q, 13q, 21q, and 22q). (C) FISH
using the telomeric repeat, (TTAGGG)n. The
twin spot signals at the fusion point of der(7)t(1;7)(q21;p22) are
indicated by an arrow.
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Identification of the telomeric repeats at the fusion point.
To determine whether the donor segment actually jumped and fused with
the telomeric repeat of the various acceptor chromosomes, we performed
a fluorescence in situ hybridization of the telomeric repeat
(TTAGGG)n, with the metaphase chromosomes of JT. In
normal human cells, the telomeric repeat signal is only observed at the chromosome ends.17 As indicated in Fig 1C, we detected the
telomeric repeat at the fusion point in addition to the two terminal
telomeres in the JT chromosome. This result was further confirmed by
Southern blot analysis. Genomic DNAs from the peripheral blood cells of the patient and a normal individual were first digested by the exonuclease BAL31 to erase the terminal telomeric repeat. This was
followed by restriction digestion with Hinf I. These digested DNAs were blotted onto a nylon membrane and hybridized with the telomeric repeat. Generally, the BAL31-insensitive hybridization signals represent internal, nonterminal sequences (Fig
2A). We observed two hybridization signals
(4.4 kb and 5.5 kb) specifically associated with the DNAs from the JT
patient (Fig 2B). These hybridization signals did not appear in the DNA
sample obtained after the frequency of JT had decreased (April 1995, see Table 1), or in DNA from the normal individual. Similar additional
signals specific to JTs were also observed when the DNAs were digested
with Tsp509 I (6 kb and 7 kb) or EcoT14 I (6 kb and 7 kb) (data not shown). We considered these BAL31-insensitive,
JT-specific fragments to be derived from the fusion points of JT
chromosomes. These results indicate that JT comprises the donor region
fused with the telomeric repeats of each acceptor chromosome.
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| Fig 2.
Southern blot analysis of the jumping translocation. (A)
BAL31 exonuclease treatment of normal genomic DNA. A longer incubation time with BAL31 exonuclease (indicated in minutes at the top of the
lanes) reduces the signal of the terminal telomeric repeat and results
in the appearance of the internal TTAGGG-fragments. (B) Southern blot
analysis of DNAs from the JT patient and a normal individual using the
telomeric repeat as a probe. The DNAs were digested with BAL31
exonuclease, followed by the Hinf I restriction. Arrows
indicate the JT-specific fragments (4.4 kb and 5.5 kb). (C) Southern
blot analysis of DNAs from the patient and a normal individual using
the nontelomeric probe A (see Fig 3a). The DNAs were digested with
EcoT14 I. Arrows indicate the JT-specific fragments (6.0 kb and
7.0 kb). The arrowhead indicates the fragment derived from the normal
allele (2 kb).
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Molecular cloning of the fusion point.
To isolate these JT-specific, TTAGGG-positive DNA fragments, genomic
libraries were constructed from size-fractionated Tsp509 I- or
EcoT14 I-restricted DNAs derived from the patient, and these were screened using the telomeric probes. Two overlapping clones were
obtained and a composite restriction map was made (indicated as jumping
translocation in Fig 3A). A region with a
unique nucleotide sequence was found adjacent to the telomeric repeats.
Southern blot analysis using this nontelomeric sequence (indicated as
"probe A" in Fig 3A) identified three DNA fragments in the
EcoT14I-restricted patient's DNA. Two bands of 6 kb and 7 kb
were specifically associated with the JT DNA, but not with the DNA
derived from a normal individual (Fig 2C). These bands were identical
with the EcoT14 I-restricted bands detected by the telomeric
probe described above. A third band of 2 kb detected by the probe A was
present in both the patient and the normal individual, and this was not
detected by the telomeric probe (Fig 2C and data not shown). These
results suggested that the 6- and 7-kb bands were derived from the
fusion points of JTs involving different acceptor chromosomes, and that
the 2-kb band originated from the normal allele of the jumped sequence,
that is 1q21. A panel of mouse/human hybrid cells was examined with probe A by PCR and Southern blot analysis. The results were consistent with the hypothesis that the probe A was derived from chromosome 1. Clones were isolated from a human genomic library using probe A. Sequence analysis of these clones showed that the location of the
fusion point is between D1S3384 and D1S2463. These two STS markers were
found in a CEPH mega-YAC clone, 955_e_11 that had been previously
mapped to 1q21.18 Taken together, these results indicated
that the JT-specific fragments we cloned represent the fusion point of
the JT chromosomes.
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| Fig 3.
Structure of the fusion point. (A) Restriction maps of
the JT-specific fragment and the normal 1q21 allele. The restriction enzymes used are: B, Bgl I; E, EcoT14 I; H,
Hinf I; T, Tsp509 I. The position of probe A is shown.
(B) The nucleotide sequences of the fusion point of the jumping
translocation. The fusion point of 1q21 was determined by a sequence
comparison between the JT-specific fragment and the normal 1q21 allele.
The telomeric regions (indicated by capital letters) found at the
fusion point were composed of variant repeats, such as TTGGGG, TGAGGG,
and TCAGGG (indicated by italic letters), along with the authentic
telomeric repeats (TTAGGG). The subtelomeric sequence distal to the
variant repeat is underlined. The unique nucleotide sequence derived
from 1q21 is indicated by small letters.
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Critically shortened telomeres involved in JT.
We determined the nucleotide sequences of the regions around the fusion
point both in the JT and the normal allele of chromosome 1 (Fig 3B).
The JT sequence had regions which consisted of telomeric repeats
(indicated by capital letters in Fig 3B) and of a unique sequence
(small letters). A short subtelomeric sequence was found between these
two regions (underlined). A comparison of this JT sequence with the
normal 1q21 sequence enabled us to pinpoint the breakpoint (Fig 3B).
Significantly, the telomeric repeats found in the JT sequence consisted
of a large number of the variant telomeric repeats TTGGGG, TGAGGG, and
TCAGGG (italics), along with the authentic TTAGGG repeats. The variant
repeats have been shown to be present in the internal region of the
telomere19-22 and proximal to a subtelomeric
sequence.23,24 This result suggested that the functional
telomere, composed of pure TTAGGG-repeats, had been completely lost
when the JT occurred.23 It has been reported that DNA
transfection of variant telomeric repeats does not result in telomeric
functions.25 Therefore, it is possible that the variant
repeats exposed at the telomeres in the leukemic cells were unable to
protect the chromosomal ends from recombination; thus, JT fusion
eventually occurred.
| |
DISCUSSION |
The patient studied here had myelodysplastic syndrome (MDS) for about
10 years before the onset of the leukemia. MDS is characterized by
ineffective hematopoiesis: Although the hematopoietic stem cells in the
bone marrow continue to proliferate extensively, systemic anemia ensues
from a maturation defect in the hematopoietic precursor cells. During
this long period of MDS, the telomeres of the patient's hematopoietic
cells may have been reduced to a level at which telomere function was
actually lost in some chromosomes.26,27 These telomere
insufficiencies may have led to JT in these chromosomal tips. Excessive
telomere shortening has been reported in MDS associated with complex
karyotype and disease evolution.28
Significantly, the leukemia clones having the JT chromosomes were taken
over by an unrelated clone having a distinct karyotype during the
terminal stage (Table 1). This type of transient JT has been reported
with a case of Down syndrome.29 In this case, the patient
presented a congenital leukemoid reaction at birth. The leukemia cells
showed a normal karyotype except for the presence of trisomy 21. The
leukemoid reaction underwent a spontaneous remission, followed by the
development of acute myeloid leukemia. The leukemia cells initially
possessed a JT chromosome where the region distal to 1q21 had jumped to
the telomere of 22q. This JT appeared only transiently: the JT soon
disappeared and an unrelated leukemic clone with a complex abnormal
karyotype without JT dominated the population. The two cases of the
transient JT, the case reported in this study and the reported case of
AML in Down syndrome, share an interesting feature. During the
transition from the JT karyotype to another karyotype, the leukemia
cells did not show any apparent phenotypic change. This observation
leads to speculation that the transient JT may have not contributed to
the progression of disease, but may have been a simple reflection of
the chromosomal instability caused by telomere insufficiencies. If this
is the case, the transient nature of JT may be expected, because
chromosome abnormalities that actually contribute to the progression of
disease would eventually appear and dominate the population. It is a
possibility that the chromosomal instability represented by the JTs was
the driving force promoting this clonal evolution of leukemic cells. As
JT appears transiently, JT would be a more frequent event than previously observed: JTs may be unstable and lost from proliferating cancer cells before they can be detected.
In conclusion, the molecular structure of the chromosomal abnormality
that resulted from a loss of telomeric functions (LTF) has been
analyzed for the first time. LTF has been suggested to play a major
role in the production of abnormal chromosomes.4,27 In
rodent cells, it has been shown that gene amplifications occur via
breakage-fusion-bridge cycles that are caused by LTF.30 However, there has been no direct evidence indicating that LTF plays a
role in the progression of human cancers. This study strongly suggests
that LTF, possibly due to the sustained cell proliferation during the
premalignant stage, may actually cause chromosomal instability and
contribute to cancer cell evolution (Table 1).
| |
FOOTNOTES |
Submitted July 2, 1997;
accepted December 10, 1997.
Supported by a Grant-in-Aid for Specially Promoted Research from the
Ministry of Education, Science, Sports and Culture of the Japan, by a
Grant-in-Aid of Special Coordination Funds for Promoting Science and
Technology from the Science and Technology Agency of Japan, and by a
Grant-in-Aid from Uehara Memorial Foundation. S.H. is supported by the
Japan Society for the Promotion of Science.
Address reprint requests to Fuyuki Ishikawa, MD, Department of Life
Science, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku,
Yokohama 226, Japan.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be here-by marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We are grateful to Dr E.A. Kamei for critical reading of and comments
on the manuscript. The excellent secretarial work of M. Fukuda is also
acknowledged.
| |
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Abstract
Introduction
Abstract