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Clinical Cancer Research Vol. 11, 6489-6494, September 15, 2005
© 2005 American Association for Cancer Research

Human Cancer Biology

NUP98 Is Fused to Topoisomerase (DNA) IIß 180 kDa (TOP2B) in a Patient with Acute Myeloid Leukemia with a New t(3;11)(p24;p15)

Karin Nebral1, Helmut H. Schmidt2, Oskar A. Haas1 and Sabine Strehl1

Authors' Affiliations: 1 Children's Cancer Research Institute, Vienna, Austria and 2 Division of Hematology, Department of Internal Medicine, University Medical Center, Graz, Austria

Requests for reprints: Sabine Strehl, Children's Cancer Research Institute, Kinderspitalgasse 6, A-1090 Vienna, Austria. Phone: 43-1-40170-449; Fax: 43-1-40170-437; E-mail: sabine.strehl{at}ccri.at.


   Abstract
Top
 Abstract
Materials and Methods
 Results and Discussion
 References
 
Purpose: The nucleoporin 98 kDa (NUP98) gene has been reported to be fused to 17 different partner genes in various hematologic malignancies with 11p15 aberrations. Cytogenetic analysis of an adult de novo acute myelogenous leukemia (M5a) revealed a t(3;11)(p24;p15), suggesting rearrangement of NUP98 with a novel partner gene.

Experimental Design: Fluorescence in situ hybridization (FISH) was used to confirm the involvement of NUP98 in the t(3;11)(p24;p15). Selection of possible NUP98 partner genes was done by computer-aided analysis of the 3p24 region using the University of California Santa Cruz genome browser. Fusion gene–specific FISH and reverse transcription-PCR analyses were done to verify the presence of the new NUP98 fusion.

Results: FISH analysis using a NUP98-specific clone showed a split signal, indicating that the NUP98 gene was affected by the translocation. Of the genes localized at 3p24, TOP2B was selected as a possible fusion partner candidate gene. Dual-color fusion gene–specific FISH and reverse transcription-PCR analysis verified that NUP98 was indeed fused to TOP2B. In addition to reciprocal NUP98-TOP2B and TOP2B-NUP98 in-frame fusion transcripts, an alternatively spliced out-of-frame TOP2B-NUP98 transcript that resulted in a premature stop codon was detected. Analysis of the genomic breakpoints revealed typical signs of nonhomologous end joining resulting from error-prone DNA repair.

Conclusions: TOP2B encodes a type II topoisomerase, which is involved in DNA transcription, replication, recombination, and mitosis, and besides TOP1, represents the second NUP98 fusion partner gene that belongs to the topoisomerase gene family. This finding emphasizes the important role of topoisomerases in malignant transformation processes.

One of the most promiscuous fusion partner genes involved in hematopoietic malignancy–associated chromosomal rearrangements is the recently identified NUP98 gene at 11p15, which to date has been discovered to fuse to 17 different partners (1). NUP98 fusions occur in de novo and therapy-related myeloid as well as lymphoid malignancies (1, 2).

NUP98 encodes a 98 kDa protein that is an important component of the nuclear pore complex, which mediates nucleocytoplasmic transport of proteins and RNA. It resides predominantly on the nucleoplasmic side of the nuclear pore complex, but was also found at the cytoplasmic face as well as dispersed within the nucleus, moving between these different localizations in a transcription-dependent manner (3–5). NUP98 consists of two NH2-terminal glycine-leucine-phenylalanine-glycine (GLFG) repeat domains (usually called FG repeats) that flank a GLEBS-like motif, which is a RAE1 binding site, and a COOH-terminal ribonucleoprotein-binding motif (6).

The most frequently observed fusion partners of NUP98 belong to the homeobox family of transcription factors and include the class I homeobox genes HOXA9, HOXA11, HOXA13, HOXC11, HOXC13, HOXD11, and HOXD13, as well as the nonclustered class II homeobox genes PRRX1/PMX1 and PRRX2 (1, 7). The HOX family genes contain a conserved helix-turn-helix motif, the homeodomain, which is fused to the NH2-terminal FG-rich region of NUP98 in all NUP98-HOX chimeric proteins reported thus far (1). NUP98-HOX fusions may deregulate expression of HOX target genes by transcriptional transactivation via NUP98 GLFG repeat–mediated recruitment of the CBP/p300 complex, and thus might influence HOX gene–regulated hematopoiesis (8, 9). The non-HOX NUP98 fusion partners compose a heterogeneous group of genes that are associated with a wide range of biological functions. In contrast to the HOX fusion partner genes, they have not been recognized to play any specific or unique role in hematopoiesis. These fusion partners include DDX10, RAP1GDS1, TOP1, PSIP2/LEDGF, NSD1, WHSC1L1/NSD3, FN1, and ADD3 (1, 2, 10). An intriguing feature of all non-HOX partners is their propensity to adopt a coiled-coil conformation (1). Most of the non-HOX NUP98 fusion partners are either transcriptional coactivators or factors that indirectly contribute to transcriptional control. Thus, oligomerization via the coiled-coil domain and/or the transactivation potential of the NUP98 GLFG repeats might confer aberrant transcriptional properties to the NUP98 fusions. This hypothesis is supported by the nuclear localization of the NUP98 fusion proteins and oligonucleotide array expression analysis (9, 11). Furthermore, the NUP98 fusions might contribute to leukemogenesis by triggering aberrant nucleocytoplasmic transport (8).

In this study, we describe the identification of the novel NUP98 partner gene TOP2B in a case of an adult de novo acute myelogenous leukemia with a t(3;11)(p24;p15). TOP2B is the second topoisomerase that fuses to NUP98, and with all non-HOX partners shares the high propensity to adopt a coiled-coil conformation.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results and Discussion
 References
 
Case history. A 63-year-old male suffered from thrombocytopenia of unclear genesis and continuous difficulty swallowing. After biopsy of the pharynx, immunohistochemistry revealed an extramedullary myeloid cell infiltrate with a French-American-British acute myelogenous leukemia M5a phenotype. The blast cells were negative for the B-cell markers CD20 and CD21, immunoglobulin {kappa} and {lambda}, as well as for the T-cell markers CD45RO and CD3, and CD15, CD30, and S-100; but positive for CD43 and CD68. Bone marrow and peripheral blood showed 80% and 99% blast cells, respectively, positive for the myeloid markers HLA-DR, CD13, and CD33, as well as CD68. Cytogenetic analysis revealed a 46,XY,t(3;11)(p24;p15) karyotype. Induction therapy with Ara-C (Cytosar-U), amsacrine, and thioguanine failed to significantly reduce the tumor load. After additional high-dose chemotherapy with Ara-C and novantrone, the patient achieved complete histologic remission but relapsed 15 months after diagnosis and showed a 90% blast cell infiltration in the bone marrow. The blast cells were resistant to Ara-C and topotecan (Hycamtin) and the patient died 20 months after initial diagnosis.

Conventional and molecular cytogenetics. Cytogenetic analysis was done on GTG-banded metaphases and karyotypes were described according to the International System for Human Cytogenetic Nomenclature (ISCN, 1995; ref. 12). Detection of the NUP98-TOP2B rearrangement was done using PAC 1173K1 (13) in combination with the TOP2B-specific RP11-659P16 clone (obtained from Dr. Mariano Rocchi, Department of Cytogenetics, University of Bari, Bari, Italy) which spans the TOP2B gene. Probes were differentially labeled by nick translation: the NUP98 probe with digoxigenin-11-dUTP and the TOP2B clone with biotin-16-dUTP (Roche Diagnostics, Vienna, Austria). Slides for fluorescence in situ hybridization (FISH) were prepared from the methanol/acetic acid–fixed cell suspension used for cytogenetic analysis and FISH was done as previously described (14). All samples were evaluated using an Axioplan fluorescence microscope (Zeiss, Vienna, Austria) equipped with the appropriate filter sets for FITC, Cy3, and 4',6-diamidino-2-phenylindole, and images were taken with a CCD camera (Photometrix, Tucson, AZ) using the IPLab software (Vysis, Inc., Stuttgart, Germany).

Reverse transcription-PCR analysis. Total RNA was extracted from peripheral blood cells obtained at diagnosis of the patient and from peripheral blood cells of a healthy individual using the Qiagen RNeasy Mini Kit (Qiagen, Inc., Vienna, Austria) according to the recommendations of the manufacturer. RNA was reverse transcribed using random hexamers and 200 units of Moloney murine leukemia virus reverse transcriptase (Invitrogen, Lofer, Austria) at 42°C for 60 minutes. The NUP98-TOP2B fusion transcript was detected using NUP98ex12 and TOP2Bex28 primers, and the reciprocal TOP2B-NUP98 using TOP2Bex24 and NUP98ex14 primers (Table 1). Expression of the normal TOP2B allele was detected using TOP2Bex24 and TOP2Bex28 primers. All reverse transcription-PCR reactions were done using Hot Start Taq Polymerase (Qiagen) and an initial activation step at 95°C for 14 minutes. Cycling conditions for all reverse transcription-PCR reactions were as follows: denaturation at 95°C for 30 seconds, annealing at 63°C for 30 seconds, and elongation at 72°C for 60 seconds carried out for 40 cycles, followed by a final extension at 72°C for 7 minutes. Sequencing of the PCR products was done by MWG Biotech (Ebersberg, Germany) and VBC-Genomics (Vienna, Austria).


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  		Table 1. Oligonucleotide primer sequences

 
Long-range PCR. The genomic breakpoints of the der(11) and der(3) chromosomes were identified by long-range PCR of genomic DNA using primers NUP98ex13 and TOP2Bex26, and TOP2Bin25-5 and NUP98in13-4, respectively (extension at 68°C for 5 minutes). Amplification of NUP98 and TOP2B normal alleles was done using NUP98in13 and NUP98in13-4, and TOP2Bin25-5 and TOP2Bin25-4 primers, respectively (Table 1).


   Results and Discussion
Top
 Abstract
 Materials and Methods
 Results and Discussion
References
 
Cytogenetic analysis revealed a t(3;11)(p24;p15) translocation in a patient with acute myelogenous leukemia M5a. Subsequent FISH analysis with the NUP98-specific clone 1173K1 showed a split signal, suggesting that NUP98 was disrupted as a result of the translocation (15). To identify candidate partner genes, computer-aided analysis of the 3p24 region using the University of California Santa Cruz genome browser3 was done and this analysis determined that roughly 35 reference sequence derived genes are localized at 3p24. Of these genes, TOP2B seemed to be an excellent candidate gene because TOP1 has already been identified as a NUP98 fusion partner (16). Dual-color FISH analysis with the NUP98 clone and a TOP2B-specific BAC resulted in two fusion signals in metaphase and interphase cells, providing compelling evidence that NUP98 was indeed fused to TOP2B (Fig. 1). Fusion gene–specific reverse transcription-PCR experiments using primers localized in exon 12 and exon 28 of NUP98 and TOP2B, respectively, led to the identification of an in-frame fusion of NUP98 exon 13 to TOP2B exon 26 (Fig. 2A and B). Analysis of the reciprocal TOP2B-NUP98 transcript identified two chimeric mRNA species fusing TOP2B exon 25 in-frame to NUP98 exon 14, and an alternatively spliced smaller transcript that fused TOP2B exon 24 out-of-frame to NUP98 exon 14, thereby generating a premature stop codon (Fig. 2A and B). According to the FISH data, the second alleles of both genes involved in the translocation were retained and expression of normal TOP2B (Fig. 2A) and NUP98 (data not shown) transcripts was verified by reverse transcription-PCR.



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  		Fig. 1. FISH analysis of the patient using clones 1173K1 specific for NUP98 (green) and RP11-659P16 encompassing the whole TOP2B gene (red). Metaphase (A) and interphase (B) nuclei displaying two fusion signals (A, arrows).

 


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  		Fig. 2. A, reverse transcription-PCR analysis of the NUP98/TOP2B and the reciprocal TOP2B/NUP98 fusion transcripts (left), and of the normal TOP2B allele (right). M, molecular weight marker, 100 bp ladder; lanes 1 and 4, patient; lanes 2 and 5, normal peripheral blood; lanes 3 and 6, negative control (same order on both gels). B, partial nucleotide and amino acid sequences of the NUP98/TOP2B and TOP2B/NUP98 in-frame fusions. C, schematic representation of NUP98 and TOP2B wild-type proteins, the putative chimeric NUP98/TOP2B and TOP2B/NUP98a proteins, and the TOP2B/NUP98b truncated protein. ATPase, ATPase domain; C-Term, COOH-terminal domain; DNA Breakage, DNA breakage-rejoining domain; GLEBS, GLEBS-like motif; GLFG, glycine-leucine-phenylalanine-glycine repeats; NES, functional nuclear export signal; NLS, functional nuclear localization signal; RNP, ribonucleoprotein-binding domain.

 
Analysis of the genomic breakpoints of the der(11) and der(3) chromosomes and comparison with the sequences of the corresponding non-rearranged alleles revealed a 2-bp deletion in NUP98 (GA) and a 4-bp microduplication of a short TOP2B sequence (AGTA) that was present on both derivative chromosomes (Fig. 3). The simplest interpretation of such a configuration is two double-strand DNA breaks within NUP98 (nt 1197 and 1199 of intron 13) and a 4-bp staggered break within TOP2B (nt 683-687 of intron 25), followed by nonhomologous end joining and gap repair. As previously shown, such deletions and duplications of base pairs are typical signs of nonhomologous end joining resulting from an error-prone DNA repair mechanism (17, 18). The genomic breakpoints described herein seem to differ from those detected for NUP98-TOP1 (19, 20). The fine structure of the breakpoints is also not compatible with the typical 4-bp staggered breaks caused by topoisomerase II as described by Ahuja et al. (20) in two cases with NUP98-TOP1 and t-MDS. Of note, our patient had primary leukemia and did not receive any topoisomerase II poisons.



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  		Fig. 3. Genomic sequences of germ line chromosomes 11 (NUP98) and 3 (TOP2B), and derivative chromosomes 11 and 3. All sequences are shown in 5'-3' orientation with respect to the NUP98 and TOP2B coding sequences. Nucleotides at the breakpoint junctions that are present on both derivative chromosomes are in boldface, and the 2-bp deletion in the NUP98 sequence is boxed. The breakpoints in NUP98 occurred at nucleotides 1,197 and 1,199 of intron 13, generating a deletion of nucleotides GA, and those in TOP2B at nucleotides 683 and 687 of intron 25.

 
DNA topoisomerase II (TOP2) is a nuclear phosphoprotein that controls and alters DNA topology. TOP2 is involved in chromosome condensation, chromatid separation, and in the relief of DNA torsional stress that occurs during transcription and replication (21). More specifically, TOP2 catalyzes the transient breakage and the subsequent rejoining of double-strand DNA and acts as an ATP-driven clamp that captures one DNA segment and transports it through the enzyme-bridged break in the second DNA duplex (22–24). Two closely related isoforms, TOP2A ({alpha}; 170 kDa) and TOP2B (ß; 180 kDa), have been identified in human cells (25). Although sharing about 70% amino acid identity, TOP2A and TOP2B are encoded by separate genes on 17q21 and 3p24, respectively, which are likely to have evolved through a gene duplication event (25–27). Although the catalytical mechanisms of TOP2A and TOP2B seem to be the same, considerable evidence suggests that the physiologic functions of the two isoforms differ from each other. In this regard, TOP2A and TOP2B are differentially expressed throughout the cell cycle, vary in their predominant subcellular distribution, and the tissue-specific expression pattern differs during fetal development and in adult vertebrates (28–33).

Several lines of evidence suggest that topoisomerase expression is associated with resistance to anticancer drugs in that topoisomerase-targeting drugs stabilize the TOP2B enzyme/DNA complex, resulting in the accumulation of DNA lesions and cell death via apoptosis (34). Chemotherapy resistance might thus be related to altered or reduced topoisomerase expression. However, in particular in leukemia, no obvious correlation between the levels of TOP2A and/or TOP2B mRNA and protein expression and chemotherapy failure could be determined (34).

Protein analyses revealed that type II DNA topoisomerases exist as homodimers, with each subunit consisting of three functional domains: an NH2-terminal ATPase domain (encoded by TOP2B exons 1-11), a central DNA breakage-rejoining domain (TOP2B exons 12-28), which contains a nucleotide-binding motif and the catalytic tyrosine (TOP2B exon 20), and a relatively poorly conserved COOH-terminal domain (TOP2B exons 29-36; refs. 22, 35). The COOH termini of the two TOP2 isoforms seem to be important for subcellular localization, and functional bipartite nuclear localization signal sequences as well as nuclear export signals are localized in these domains (36, 37).

The NUP98-TOP2B fusion transcript fuses the NH2-terminal FG repeat and GLEBS motifs of NUP98 with the COOH-terminal domain of TOP2B, thereby retaining the functional nuclear localization signal but eliminating the nuclear export signals (Fig. 2C). Consequently, the putative reciprocal TOP2B-NUP98 chimeric protein retains the ATPase, the DNA breakage-rejoining, and the nuclear export signal domains of TOP2B that are fused to the ribonucleoprotein-binding and nuclear localization signal domains of NUP98 (Fig. 2C). The shorter out-of-frame TOP2Bexon24-NUP98exon14 fusion transcript might encode a truncated TOP2B isoform that consists of the ATPase, the DNA breakage-rejoining, and nuclear export signal domains fused to 18 fusion partner unrelated amino acids (Fig. 2C). It is unclear in which way the NUP98-TOP2B protein contributes to oncogenic transformation, and if the putative reciprocal TOP2B-NUP98 and/or the truncated TOP2B isoform plays an essential role in this process. In a significant number of cases with NUP98 fusions, the reciprocal partner-NUP98 transcript is absent, which indicates that the NUP98-partner fusion protein is critical for the leukemic transformation process (1, 2).

The unifying feature of all NUP98 fusion proteins is that the NH2-terminal FG repeats, which have a strong transcriptional transactivation potential through direct interaction with the CBP/p300, are always fused to different partner proteins (1). In particular, malignant transformation induced by expression of NUP98-HOX chimeric proteins seems to be caused by aberrant transcriptional regulation of target genes (8, 11, 38). In contrast, the oncogenic mechanism of NUP98 fusions that involve non-HOX partner genes seems to differ from that described for HOX partners because most of these fusion partners have neither direct DNA binding properties nor are they implicated in hematopoietic development. All proteins encoded by non-HOX NUP98 fusion partners described to date contain regions with a significant probability to adopt a coiled-coil conformation. These domains, which are present in ~3% to 5% of all human proteins and are thought to be involved in homo- and heterodimerization (39), are retained in the chimeric proteins and fused to the transactivating FG repeat–rich NH2 terminus of NUP98 (1, 40). Protein analysis with the COILS 2.2 (39)4 and the MULTICOIL (41)5 programs revealed this intriguing feature also in the COOH-terminal region of TOP2B between amino acids 1,150 to 1,175 (P = 1.0) and 1,148 to 1,174 (P = 0.55), respectively.

Regarding the other NUP98 topoisomerase fusion partner, TOP1, recent findings have shown that engineered expression of NUP98-TOP1 results in rapid perturbations of hematopoiesis (9). Strikingly, these perturbations seemed to be independent of TOP1 catalytic activity because a mutation known to abrogate TOP1 DNA isomerase activity essentially did not alter the NUP98-TOP1 proliferative and oncogenic potential. These data suggest that leukemogenic transformation does not occur through up-regulated TOP1 DNA unwinding activity. In addition, no genome instability was observed, and thus NUP98-TOP1 expression does not seem to interfere with normal TOP1 activity. Therefore, the transcriptional coactivator property of TOP1 provides a possible functional similarity to HOX genes in that the NUP98-TOP1 chimeric protein acts as an aberrant transcription factor (9). However, for TOP2B, no involvement in transcriptional regulation has been determined. In addition, TOP1 belongs to the type IB subfamily of topoisomerases I that share no sequence or structural homology with other known topoisomerases, and are thus functionally distinct (42). Moreover, the NUP98-TOP1 and the NUP98-TOP2B fusion proteins differ significantly from each other in that virtually all of the TOP1 proteins (amino acids 170-514) containing the core, the linker, and the COOH-terminal domains but only the TOP2B COOH terminus, respectively, are fused to the FG repeat motif of NUP98.

Interestingly, complete disruption of the nucleoplasmically oriented NUP98 protein triggers dramatic changes at the cytoplasmic face of the nuclear pore complex and causes distinct protein import pathways to operate with reduced efficiency (43). However, the NUP98 chimeric proteins analyzed (HOXA9, PMX1, RAP1GDS1, and TOP1) were localized in the nucleus. Whether disturbances of the nucleocytoplasmic transport are caused by NUP98 fusions has not been investigated to date. Intriguingly, recent investigations of a nucleoporin NUP214 rearrangement suggest that the SET-NUP214 fusion protein, which also resides in the nucleus, leads to disorganization of nuclear export by causing aberrant localization of CRM1 (XPO1, exportin 1; ref. 44). In this context, in vitro studies of NUP98 showed interactions with various export factors such as RaeI/Gle2, Mex67p/Mtr2p, TAP, and also CRM1 (1). Thus, it cannot be entirely ruled out that at least some of the NUP98 chimeric proteins interfere with appropriate nucleocytoplasmic shuttling.

In conclusion, the identification of TOP2B as the second NUP98 topoisomerase fusion partner confirms and extends the previously recognized important role of topoisomerases in malignant transformation processes as well as chemotherapy resistance mechanisms. In line with the vast majority of NUP98 gene rearrangements, the fusion with TOP2B was detected in an acute leukemia derived from the myeloid lineage. Further extensive functional analyses of NUP98 fusion proteins are needed to elucidate the complex pathways of NUP98-associated leukemogenesis.


   Acknowledgments
 
We thank Rolf Marschalek for his expertise in the analysis of the genomic breakpoints of the translocation.


   Footnotes
 
Grant support: "Österreichische Kinderkrebshilfe" and the research program "Genome Research for Health" of the Austrian Ministry of Education, Science, and Culture (GEN-AU Child, GZ 200.071/3-VI/2a/2002).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

3 http://genome.ucsc.edu/. Back

4 http://www.ch.embnet.org/software/COILS_form.html. Back

5 http://multicoil.lcs.mit.edu/cgi-bin/multicoil. Back

Received 1/20/05; revised 5/17/05; accepted 6/20/05.


   References
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 Abstract
 Materials and Methods
 Results and Discussion
 References
 

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