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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3258-3261
The t(11;20)(p15;q11) Chromosomal Translocation Associated With
Therapy-Related Myelodysplastic Syndrome Results in an
NUP98-TOP1 Fusion
By
Harish G. Ahuja,
Carolyn A. Felix, and
Peter D. Aplan
From the Departments of Medicine, Pediatrics, and
Cancer Genetics, Roswell Park Cancer Institute,
Buffalo, NY; the Division of Oncology,
The Children's Hospital of Philadelphia, University
of Pennsylvania School of Medicine, Philadelphia, PA; and
the Division of Hematology/Oncology, Children's
Hospital of Buffalo, Buffalo, NY.
 |
ABSTRACT |
The NUP98 gene is involved in 3 distinct chromosomal
rearrangements, t(7;11)(p15;p15), t(2;11)(q31;p15), and
inv(11)(p15q22); all of these NUP98 rearrangements have been
identified in the malignant cells of patients with therapy-related
acute myelogenous leukemia or myelodysplastic syndrome (t-AML/MDS).
Here we report the cloning and characterization of a t(11;20)(p15;q11)
translocation from patients with t-MDS. The breakpoint on chromosome
11p15 targets the NUP98 gene and results in the separation of
the N-terminal FXFG repeats from the RNA-binding domain located in the
C-terminus. The breakpoint on chromosome 20q11 occurs within the gene
encoding human DNA topoisomerase I (TOP1). As a result, a
chimeric mRNA encoding the NUP98 FXFG repeats fused to the body of DNA
topoisomerase I is produced. These results indicate that NUP98
is a recurrent target in therapy-related malignancies, and that
TOP1 is a previously unrecognized target for chromosomal translocations.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
NONRANDOM CHROMOSOMAL aberrations such as
translocations, deletions, and inversions are associated with a wide
variety of hematological malignancies and are considered causal events in the process of leukemic transformation.1 In some
instances, chromosomal translocations fuse sequences encoding a
transcription factor or receptor tyrosine kinase to those of a normally
unrelated gene, resulting in a chimeric protein with oncogenic
properties. In other cases, the translocations result in the coding
regions of proto-oncogenes becoming joined to, and regulated by, highly active promoter/enhancer elements such as those of the Ig or T-cell receptor genes.1 Similar chromosomal aberrations associated with therapy-related myelodysplastic syndromes and therapy-related acute myelogenous leukemia (t-MDS/AML) are thought to arise as a direct
result of exposure to various forms of chemotherapy and/or radiation
therapy.2 Agents that target DNA topoisomerase II (topo II)
are associated with a distinct form of t-AML, characterized by a short
latency period, monocytic features, and balanced translocations involving the MLL gene on chromosome 11q23.3 Other
balanced translocations such as t(8;21),4
t(15;17),5 and inv(16)6 have also been
reproducibly associated with t-AML after exposure to multiagent chemotherapy.
The NUP98 gene encodes a 98-kD component of the
nuclear pore complex (NPC) that is localized to the nucleoplasmic side
of the NPC.7 It is thought to function as a docking protein
involved in nucleocytoplasmic transport7; this docking
function is mediated, at least in part, by multiple FXFG repeats
located in the N-terminal portion of the protein.7 We and
others have recently reported that the NUP98 gene is found at
the breakpoints of 3 distinct chromosomal rearrangements: the
t(7;11)(p15;p15),8,9 t(2;11)(q31;p15),10 and
inv(11)(p15q22).11 Chimeric mRNAs produced by the t(7;11) and the t(2;11) fuse the FXFG repeats of NUP98 with the homeodomains of
HOXA9 and HOXD13, respectively, while the
inv(11)(p15q22) fuses the NUP98 FXFG repeats with
DDX10, a putative RNA helicase.8-11 Significantly,
all of these translocations have been reported to occur in the leukemic
cells of patients with t-MDS/AML.10-12 Based on the above
findings, we hypothesized that the NUP98 gene would be
disrupted in the t(11;20) translocation, and that a chimeric gene
fusing the NUP98 sequences in frame to a gene on chromosome 20q11 would
be produced as a result of the translocation.
| |
MATERIALS AND METHODS |
Case reports.
Patient no. 923 was a 4-year-old girl who was diagnosed with acute
lymphoblastic leukemia; the leukemic cells showed a normal karyotype.
She received multiagent chemotherapy that included daunorubicin,
vincristine, cortisone, L-asparaginase, doxorubicin, cyclophosphamide,
6-mercaptopurine, methotrexate, etoposide, and cytosine arabinoside.
Nine years later, she developed an MDS (French-American-British [FAB]
type RAEB-t); the karyotype was 46, XX,
t(11;20)(p15;q11.2). This patient has previously been reported in a
series of t-AML patients (patient no. 14 in ref 13), and had an
MLL gene pseudorearrangement. Patient no. 1138 was a
15-year-old boy who was diagnosed with non-Hodgkin's lymphoma and
received therapy with doxorubicin, vincristine, cyclophosphamide,
cortisone, etoposide, ifosphamide, cytosine arabinoside, cisplatin,
L-asparaginase, and methotrexate. Approximately 14 months after
initiation of treatment, an MDS (FAB type RAEB) was diagnosed.
Cytogenetic analysis showed a 46, XY, t(11; 20) (p15;q11.2) [17]/45,
idem,  5[3]. This patient has also been previously reported
(patient no. 34 in ref 14).
Nucleic acid isolation.
Genomic DNA and total RNA was extracted from cryopreserved leukemic
cells as previously described.10 Control DNA and RNA were
obtained from peripheral blood mononuclear cells (PBMC) obtained from a
normal volunteer. The studies performed were approved by the
Institutional Review Board of Roswell Park Cancer Institute, and
informed consent for use of patient material in research studies was
obtained by the referring institution.
3'-RACE.
3'-RACE was performed using reagents from Life Technologies, Inc
(Gaithersburg, MD) and a modified protocol as described
previously.10 The polymerase chain reaction (PCR) was
performed using an NUP98-specific forward primer (NUP8001,
Table 1) and an abridged universal AP (AUAP, Table 1) as the reverse primer. The PCR products were analyzed
by hybridization to a terminal deoxynucleotidyl transferase (TdT)
end-labeled nested NUP98 oligonucleotide (NUP8002, Table 1) as
described previously.10 The PCR products were cloned into
the pGEM T-Easy vector using the reagents and protocols supplied by the
manufacturer (Promega, Madison, WI). Positive clones
were identified by filter lift hybridization to the NUP8002
oligonucleotide.
Reverse-transcriptase (RT)-PCR analysis.
First-strand cDNA was synthesized as described
previously.10 An NUP98 sense primer (NUP8002) and a
TOP1 antisense primer (HA-05, Table 1) were used along with
Advantage Taq polymerase and reagents (Clontech, Palo Alto,
CA). The PCR thermal cycling protocol consisted of
94°C for 1 minute, followed by 35 cycles of 94°C for 30 seconds and
68°C for 6 minutes. The PCR products were subcloned into the pGEM
T-Easy (Promega, Madison, WI) vector and sequenced using a Perkin-Elmer
ABI PRISM Model 373A Stretch Automated sequencer.
(Applied Biosystems, Foster City, CA).
| |
RESULTS AND DISCUSSION |
The NUP98 gene was found to be rearranged in the leukemic cells
of both patient samples on Southern blot hybridization of genomic DNA
to an NUP98 cDNA probe (unpublished observations). To
identify a potential fusion transcript involving NUP98, we used
3'-RACE on RNA isolated from patient no. 923. The choice of the
NUP98-specific forward primer (NUP8001, Table 1) was based on
previously reported NUP98 fusions that occurred at either
nucleotide 1552 or 1864 (Genbank accession no. U41815) and on our
reasoning that the t(11;20) might produce a transcript with a similar
fusion point. The PCR products were subcloned into plasmid vectors, and a clone that hybridized to an internal NUP98 oligonucleotide
(NUP8002, Table 1) was selected for further analysis.
The nucleotide sequence of this 3'-RACE clone diverged from the
germline NUP98 sequence at nucleotide 1686 (Genbank accession no. U41815). A BLAST search showed that the sequence immediately 3' of
this divergence was a perfect match for the gene encoding human DNA
topoisomerase I (TOP1; GenBank accession no. J03250). The
resultant in-frame fusion mRNA joined nucleotide 1686 of NUP98 to nucleotide 719 of TOP1 (Fig 1A). The
predicted chimeric protein would contain the N-terminus of NUP98,
including the FXFG repeats (amino acids 1-514) fused to the majority of
DNA topoisomerase I (amino acids 170-765) including the core, linker,
and catalytic domains (Fig 1B). We were unable to amplify a potential
reciprocal TOP1-NUP98 fusion encoding the DNA topoisomerase I
N-terminus and the NUP98 RNA binding domain. These results are
consistent with previous reports of NUP98 fusions that have
consistently detected N-terminus NUP98 sequences fused to C-terminus
partner gene sequences, but not N-terminus partner gene sequences fused to C-terminus NUP98 sequences.8-12
View larger version (77K):
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| Fig 1.
NUP98-TOP1 fusion cDNA. (A) NUP98-TOP1
fusion sequence. The germline NUP98 and TOP1 (bold and
italic) nucleotide sequences are as shown. The NUP98-TOP1
fusion cDNA is as indicated. The amino acids encoded are shown below
the nucleotide sequence. (B) Schematic representation of the wild-type
and fusion proteins. Functional domains indicated for NUP98 are FXFG,
FXFG repeat region; and RNA bind, RNA binding domain. DNA topoisomerase
I N-terminus, core, linker, and C-terminus domains, as designated in
ref 19, are indicated. NUP98 and TOP1 fusion points are shown with
vertical arrows. (C) RT-PCR assay for NUP98-TOP1 fusion mRNA.
Primers NUP8002 and HA-05 were used to amplify the 1,677-bp fusion
mRNA. Patient samples no. 923 and 1138 are as indicated; no specific
PCR product is seen in the negative control lanes (K562, HL60, Jurkat,
H2O).
|
|
To exclude the possibility of a PCR artifact leading to the
NUP98-TOP1 fusion, and to determine if NUP98-TOP1
fusion transcripts could be detected in additional patient samples, we
designed gene-specific RT-PCR primer pairs (primers NUP8002 and HA-05;
Table 1) to amplify the fusion mRNA. As shown in Fig 1C, we were able
to amplify identical 1,677-bp PCR products from both patient samples,
but not from the control cell lines, showing that identical chimeric
transcripts were produced in both patient samples. Sequence analysis
confirmed that an identical fusion cDNA was produced in both samples.
We were able to successfully amplify the germline NUP98 cDNA sequence from both the patient samples and control cell lines, using primers NUP8001 and NUP8006 (Table 1), demonstrating that both NUP98 alleles
were expressed, and confirming the presence of intact RNA in the
control samples (data not shown).
The t(11;20)(p15;q11.2) is a rare but recurrent translocation that has
been reported in patients with MDS,13 AML,15
and polycythemia vera.16 The 2 patients reported here were
children who had developed t-MDS/AML after treatment with multi-agent
chemotherapy. Of note, the t(2;11) and inv(11)(p15q22) that involve
NUP98 were both initially recognized in pediatric patients with
t-MDS/AML.10,17 In addition, although the t(7;11) has been
most frequently recognized in patients with de novo AML, there is a
recent report of t-AML with a t(7;11) after the use of the topo II
poison bimolane (ICRF 154) for psoriasis.12 Furthermore, a
recent review of children with t-MDS/AML identified 11p15 abnormalities
in 7% of patients.18 Taken together, these data suggest
that NUP98 may be a more frequent target for therapy-related
chromosomal translocations than previously thought, especially in children.
This report provides the first data to suggest that deregulation of DNA
topoisomerase I function may be directly related to malignant
transformation. DNA topoisomerase I normally catalyzes a cycle of
transesterification reactions during which it generates transient
single-stranded DNA nicks, resulting in topological transformations of
DNA.19,20 DNA topoisomerase I has been shown to be involved
in DNA replication, transcription, and recombination, as well as
chromosome condensation.19,20 The DNA topoisomerase I
protein can be organized into 4 distinct domains: a C-terminus catalytic region that contains the active tyrosine, a nonconserved "linker" domain, a conserved "core" domain, and an
N-terminus domain that contains a nuclear localization signal
(NLS).20 The core domain has been shown to mediate binding
to supercoiled DNA, whereas the N-terminus domain, which is largely
lost in the NUP98-TOP1 fusion, is dispensable for DNA
topoisomerase I catalytic function in vitro.19-21 However,
several recent studies have suggested that the N-terminus domain may
have additional, previously unsuspected roles. The N-terminus domain
has been shown to interact with nucleolin,22 SV40 large T
antigen,23 and the SF2/ASF splicing
factor.24 Additionally, DNA topoisomerase I has recently
been shown to interact with the C-terminus of p5325;
however, the region of DNA topoisomerase I that interacts with p53 is unknown.
The mechanism by which an NUP98-TOP1 fusion might be
leukemogenic is unknown. Chromosomal translocations that generate
fusion proteins are generally thought to be oncogenic through a gain of
function attributed to the fusion protein. Because the predicted NUP98-TOP1 fusion protein lacks the N-terminus of DNA topoisomerase I,
loss of regulatory functions dependent on the DNA topoisomerase I
N-terminus may lead to a gain of function through the fusion of NUP98
sequences to the catalytic portion of DNA topoisomerase I. Alternatively, it is possible that an NUP98-TOP1 fusion protein binds
to and sequesters a protein that normally binds DNA topoisomerase I
such as p53. Lastly, it has recently been shown that an NUP98-HOXA9 fusion protein can transform NIH3T3 fibroblasts in vitro.26 The mechanism suggested in those experiments is that HOXA9-responsive genes are activated by the NUP98-HOXA9 fusion through a previously unrecognized NUP98 transactivation domain present in the NUP98 FXFG
repeat region. However, it is difficult to envision how an NUP98-TOP1
fusion protein could activate transcription in a sequence-specific fashion.
In summary, we have cloned a t(11;20) chromosomal translocation that
results in a previously undescribed, in-frame fusion between NUP98 and
TOP1. The mechanism by which a NUP98-TOP1 fusion protein might be
transforming is unknown and can only be answered by future experiments,
although the precedent set by other leukemogenic fusion proteins might
suggest that it acts dominantly, through a gain of function. Finally,
the finding that this translocation, as well as at least 3 other forms
of balanced NUP98 chromosomal rearrangements, occurred in patients with
t-MDS/AML suggests that NUP98 is a recurrent target for chromosomal
rearrangements caused by genotoxic therapy.
| |
ACKNOWLEDGMENT |
We thank Ronald Hancock, Ilan Kirsch, and William Burhans for helpful
discussions, Julian Borrows for the NUP98 cDNA probe, and
Robert Bash, Naomi Winick, Allan Pyesmany, Thomas Nevill, and Rebecca
Eisan for providing patient specimens and clinical information. We also
thank Elena Greco for artwork.
| |
FOOTNOTES |
Submitted May 27, 1999; accepted June 29, 1999.
P.D.A. is supported by a Leukemia Society of American Scholar Award and
National Institutes of Health (NIH) Grants No. CA16056 and CA73773.
C.A.F. is supported by a Leukemia Society of America Scholar Award and
NIH Grants No. CA66140, CA77683, and CA80175.
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 Peter D. Aplan, MD, Department of
Pediatrics, Roswell Park Cancer Institute, Buffalo, NY 14263; e-mail:
paplan{at}sc3101.med.buffalo.edu.
| |
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33 - 37.
[Abstract]
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R. J. Jaju, C. Fidler, O. A. Haas, A. J. Strickson, F. Watkins, K. Clark, N. C. P. Cross, J.-F. Cheng, P. D. Aplan, L. Kearney, et al.
A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia
Blood,
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[Abstract]
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H. G. Ahuja, J. Hong, P. D. Aplan, L. Tcheurekdjian, S. J. Forman, and M. L. Slovak
t(9;11)(p22;p15) in Acute Myeloid Leukemia Results in a Fusion between NUP98 and the Gene Encoding Transcriptional Coactivators p52 and p75-Lens Epithelium-derived Growth Factor (LEDGF)
Cancer Res.,
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[Abstract]
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B. M. A. Fontoura, G. Blobel, and N. R. Yaseen
The Nucleoporin Nup98 Is a Site for GDP/GTP Exchange on Ran and Termination of Karyopherin beta 2-mediated Nuclear Import
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TOP
ABSTRACT
INTRODUCTION