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[Cancer Research 62, 4571-4574, August 15, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

Novel NUP98-HOXC11 Fusion Gene Resulted from a Chromosomal Break within Exon 1 of HOXC11 in Acute Myeloid Leukemia with t(11;12)(p15;q13)1

Takeshi Taketani, Tomohiko Taki, Noriko Shibuya, Akira Kikuchi, Ryoji Hanada and Yasuhide Hayashi2

Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan [T. Take., T. Taki, N. S., Y. H.]; Department of Pediatrics, Shimane Medical University, Shimane 693-8501, Japan [T. Take.]; and Division of Hematology/Oncology, Saitama Children’s Medical Center, Saitama 339-8551, Japan [A. K., R. H.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
The NUP98 gene has been reported to be fused to 11 partner genes in hematological malignancies with 11p15 translocations. Among NUP98 fusion partner genes, HOXA and HOXD clusters have been reported thus far; however, no HOXC or HOXB clusters have been reported. We identified a novel NUP98-HOXC11 fusion gene in a pediatric patient with de novo acute myeloid leukemia having t(11;12)(p15;q13). The breakpoint of NUP98 was located within a LINE repetitive sequence (HAL1) in intron 12, and the breakpoint of HOXC11 was located within exon 1, resulting in a NUP98-HOXC11 in-frame fusion transcript containing exon 12 of NUP98 fused to a part of exon 1 of HOXC11 with an 8-bp insertion derived from the intron sequence just 5' of the breakpoint of NUP98. The NUP98-HOXC11 fusion protein consists of the NH2-terminal phenylalanine-glycine repeat motif of NUP98 and the COOH-terminal homeodomain of HOXC11. Although the frequency of HOXC11 expression was not high in leukemia cell lines, its expression was significantly more frequent in myeloid than lymphoid leukemia cell lines. These data suggest that the NUP98-HOXC11 fusion protein plays a role in the pathogenesis of myeloid malignancies.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
A great number of recurrent chromosomal translocations are related to leukemia and myelodysplastic syndrome (1 , 2) . Remarkable progress in molecular genetics has brought a better understanding of several genes involved in these translocations. Recently, leukemia and myelodysplastic syndrome with chromosome 11p15 translocations have been reported to involve the NUP98 gene (2 , 3) . To date, 11 different partner genes fused to NUP98 have been identified (2, 3, 4, 5, 6, 7, 8, 9, 10) .

NUP98 is a Mr 98,000 component of the nuclear pore complex located on its nucleoplasmic side, and it selectively transports RNA and protein between the nucleus and cytoplasm (11) . The HOX genes are transcriptional factors for which the regulation of embryonic morphological development is required (12) . Human class I HOX genes belonging to four different clusters (A, B, C, and D) are located on chromosomes 7, 17, 12, and 2, respectively. Among NUP98 fusion partner genes, five class I HOX genes, HOXA9 (7p15; Refs. 4 and 5 ), HOXA11 (7p15; Ref. 9 ), HOXA13 (7p15; Refs. 9 and 10 ), HOXD13 (2q31; Ref. 6 ), and HOXD11 (2q31; Ref. 8 ), have been reported thus far. However, no HOXC or HOXB genes have been reported as yet.

Three patients with t(11;12)(p15;q13) have been reported previously (13, 14, 15) . All these patients were diagnosed as having therapy-related AML.3 We identified a novel partner gene of NUP98, HOXC11, in a de novo pediatric patient with t(11;12)(p15;q13)-AML and determined genomic breakpoints between NUP98 and HOXC11. We also report a specific expression pattern of the HOXC11 genes in various leukemia cell lines.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Patients.
A 14-year-old boy was diagnosed with AML (French-American-British classification M1), which was cytogenetically characterized as 46, XY, t(11;12)(p15;q13) in all 20 bone marrow cells examined. The WBC count at diagnosis was 12,500/µl with 87% leukemic blasts, which expressed CD13, CD33, and HLA-DR antigens. Complete remission was achieved 1 month after diagnosis by chemotherapy on the ANLL-91 protocol (16) . His karyotype showed 46, XY in all 20 bone marrow cells in remission. Nine months after diagnosis, he underwent an allogeneic BMT from a HLA-matched sibling donor and was in complete remission for 6 months. A relapse occurred in the bone marrow 7 months after BMT, and he died of progressive disease 10 months after BMT. Leukemic cells from bone marrow were obtained from the patient at diagnosis after informed consent was given.

Southern Blot Analysis.
High molecular weight DNA was extracted from bone marrow cells of the patient by proteinase K digestion and phenol/chloroform extraction (17) . Ten µg of DNA were digested with BamHI, subjected to electrophoresis on 0.7% agarose gels, and transferred to cDNA probes labeled with 32P by the random hexamer method (17) . The probes used were an 837-bp NUP98 cDNA fragment (nt 1213–2049; GenBank accession number U41815) and a 333-bp HOXC11 cDNA fragment (nt 503–835; GenBank accession number AJ000041).

RT-PCR for Identification of a Novel Partner Gene of NUP98.
To detect the 3' unknown gene fused to the 5' NUP98 gene, we adapted a RT-PCR method. Total RNA was extracted from the leukemia cells of the patient using the acid guanidinium thiocyanate-phenol chloroform method (17) . Total RNA (4 µg) was reverse-transcribed to cDNA, using a cDNA synthesis kit (Amersham Pharmacia Biotech, Buckinghamshire, England; Ref. 17 ). To test for the presence of amplifiable RNA, ß-actin was amplified using the same cDNA by RT-PCR. One µl of the cDNA solution was amplified by PCR in a total volume of 20 µl with 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, 0.001% (w/v) gelatin, 5% DMSO, 200 mM of each deoxyribonucleotide triphosphate, 2.5 units of Taq polymerase (Applied Biosystems, Foster, CA), and 10 pmol of each primer. The sense primer used for RT-PCR was NUP98-1507S (5'-ACTACGACAGCCACTTTGGG-3'), and the antisense primer was HOXC11-791AS (5'-TGCAGCCGCTTCTCTTTGTT-3'). Other HOXC cluster genes (HOXC9, HOXC10, HOXC12, and HOXC13) were also used as antisense primers. PCR amplification was performed with this mixture using a DNA thermal cycler (Applied Biosystems) under the following conditions: initial denaturation at 94°C for 9 min; 40 cycles at 96°C for 30 s, 55°C for 30 s, and 72°C for 1 min; followed by a final elongation at 72°C for 7 min.

Long PCR.
To detect genomic breakpoints between NUP98 and HOXC11, we adopted a long PCR method. One hundred ng of the DNA were amplified by PCR in a 50-µl (total volume) mixture containing 2.5 units of TaKaRaLA Taq polymerase, 400 µM of each deoxyribonucleotide triphosphate, 10x LA PCR Buffer II, 2.5 mM MgCl2 (TaKaRa Biochemical, Shiga, Japan), 5% DMSO, and 25 pmol of each primer. The sense primer used for long PCR was NUP98-1507S, and the antisense primer was HOXC11-616AS (5'-TGTTCTCCTCCTCAGCCTC-3'). For the reciprocal HOXC11-NUP98 fusion gene, the sense primer was HOXC11-459S, and the antisense primer was NUP98-int12-475AS (5'-AGCGCGAGACTCCTTTTCA-3'). PCR amplification was performed under the following conditions: preheating at 95°C for 1 min; 35 cycles of denaturation for 30 s at 95°C and annealing and extension for 3 min (increments of 15 s every cycle) at 68°C; with a final extension of 10 min at 72°C.

Nucleotide Sequencing.
PCR products were cloned into the TOPO TA cloning vector (Invitrogen, Carlsbad, CA). The nt sequences were determined by the fluorometric method (Dye Terminator Cycle Sequencing Kit; Applied Biosystems; Ref. 17 ).

RT-PCR for Examination of HOXC11 Gene Expression.
To analyze the expression pattern of the HOXC11 gene in leukemia cell lines, RT-PCR was performed. We used 69 cell lines as follows (8 , 10) : (a) 22 B-precursor ALL cell lines (UTP-L20, P30/OHK, LAZ-221, LC4-1, NALM-26, THP-4, THP-5, THP-7, THP-8, RS4;11, KOCL-44, KOCL-45, BV173, OM9;22, NALM-20, NALM-24, UTP-2, UTP-L5, REH, MV4;11, HAL-01, and KOPN-41); (b) 10 B-ALL cell lines (BALM-1, BALM-6, BALM-9, BALM-13, BALM-14, BJAB, DAUDI, RAJI, RAMOS, and BAL-KH); (c) 10 T-ALL cell lines (RPMI-8402, MOLT-14, KOPT-KI, THP-6, PEER, JURKAT, HSB-2, HPB-ALL, L-SAK, and L-SMY); (d) 9 AML cell lines (YNH-1, ML-1, KASUMI-3, KG-1, P39/TSU, inv-3, SN-1, NB4, and HEL); (e) 6 AMOL cell lines (THP-1, IMS/M1, CTS, P31/FUJ, MOLM-13, and KOCL-48); (f) 5 CML cell lines (MOLM-1, MOLM-7, TS9;22, SS9;22, and K-562); (g) 2 AMKL cell lines (CMS and CMY); and (h) 5 EBV-B cell lines derived from normal adult peripheral lymphocytes. RT-PCR mixtures were the same as those described previously (8) . PCR amplification was performed under the following conditions: preheating at 94°C for 9 min; 40 cycles of denaturation for 1 min at 95°C, annealing for 1 min at 60°C, and extension for 1 min at 72°C; with a final extension of 7 min at 72°C. The primers used for RT-PCR were HOXC11-459S and HOXC11-791AS.


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
Southern blot analysis of DNA from leukemia cells of the patient using the NUP98 probe showed a rearranged band (Fig. 1A)Citation . Thus, we concluded that the NUP98 gene in this patient was fused to a novel partner gene. Until now, class I HOX genes identified as fusion partners of NUP98 were HOXA9 (7p15; Refs. 4 and 5 ), HOXA11 (7p15; Ref. 9 ), and HOXA13 (7p15; Refs. 9 and 10 ) in AML with t(7;11)(p15;p15) and HOXD11 (2q31; Ref. 8 ) and HOXD13 (2q31; Ref. 6 ) in AML with t(2;11)(q31;p15). Human class I HOXC genes were located on chromosome 12q13. Therefore, we considered that a novel partner gene fused to NUP98 in t(11;12)(p15;q13) was one of the HOXC cluster genes. To isolate the novel partner gene of NUP98, we performed RT-PCR for total RNA from the patient’s leukemia cells. Using several antisense primers based on the HOXC cluster genes (HOXC9, HOXC10, HOXC11, HOXC12, and HOXC13), we obtained an RT-PCR product of 294 bp when NUP98-1507S and HOXC11-791AS were used (Fig. 2A)Citation . Sequence analysis showed that the RT-PCR product was an in-frame fusion transcript of NUP98-HOXC11 containing exon 12 of the NUP98 gene (up to nt 1552) fused to part of exon 1 of HOXC11 with an 8-bp insertion that existed within the intron 12 sequence of NUP98 (Fig. 2B)Citation . No reciprocal fusion transcript (HOXC11-NUP98) was detected (Fig. 2A)Citation . Southern blotting with a HOXC11 cDNA probe revealed a rearranged band in these leukemic cells (Fig. 1B)Citation .



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  		Fig. 1. Southern blotting of the NUP98 and HOXC11 genes with BglII. Arrows indicate a rearranged band of the NUP98 (A) and HOXC11 (B) genes. P, patient; C, control.

 


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  		Fig. 2. Identification of a novel NUP98 partner gene, HOXC11. A, the NUP98-HOXC11 chimeric transcript by RT-PCR. M, size marker; Pt, patient; Lane 1, NUP98-HOXC11 fusion transcript; Lane 2, HOXC11-NUP98 fusion transcript. B, nt and amino acid sequencing of NUP98, HOXC11, and NUP98-HOXC11 chimeric transcripts. Arrows indicate the fusion point. Italic letters indicate an 8-bp insertion. C, structure of the predicted NUP98, HOXC11, and NUP98-HOXC11 fusion protein. FG, FG repeats; GLEBS, Gle2p-binding like motif; HD, homeodomain. Arrows indicate the fusion point.

 
We next cloned the genomic breakpoints of NUP98 and HOXC11. Because the NUP98-HOXC11 fusion transcript contains exon 12 and a part of intron 12 of NUP98 fused to part of exon 1 of HOXC11, we supposed that the genomic breakpoints lay within intron 12 of NUP98 and the 5' side of HOXC11. Thus, we performed long PCR for DNA from the patient’s leukemic cells to clone the genomic breakpoints and obtained PCR products of 440 bp using primers NUP98-1507S and HOXC11-616AS and 240 bp using primers HOXC11-459S and NUP98-int12-475AS (Fig. 3, A and B)Citation . The 8-bp inserted sequence from the NUP98 intron existed just on the 5' side of the breakpoint (Fig. 3B)Citation . We considered that derivative chromosome 11 recognized an AG site before the 8-bp sequence derived from intron 12 of NUP98 that formed a part of the NUP98-HOXC11 fusion transcripts as a splicing acceptor site (Fig. 3B)Citation . The breakpoints at 11p15 and 12q13 were located within a LINE repetitive sequence (HAL1) in intron 12 of NUP98 and within exon 1 of HOXC11, respectively (Fig. 3C)Citation . Although microduplications were found at the genomic breakpoints of both t(2;11)(q31;p15) (18) and, t(11;20)(p15;q11) (19) , there was no microduplication, topoisomerase II consensus sequence, purine/pyrimidine repeat region, Alu repeats, translin consensus sequence, or heptamer/nonamer sequences at or near the breakpoints (Fig. 3B)Citation . The genomic breakpoints in NUP98-HOX fusion genes were clustered on intron 12 of NUP98 (19) . Repeat elements were interspersed in about 50% of intron 12. These suggested that occurrence of the NUP98-HOX fusion genes may be associated with repetitive elements of NUP98.



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  		Fig. 3. Cloning of genomic breakpoints between NUP98 and HOXC11. A, detection of the genomic fusion points of NUP98-HOXC11 (Lane 1) and HOXC11-NUP98 (Lane 2) by long PCR. M, size marker. B, nt sequencing of the breakpoints of t(11;12)(p15;q13). Chromosome 11 sequences appear in lowercase letters, and chromosome 12 sequences appear in capital letters. Italic letters indicate an 8-bp insertion of NUP98-HOXC11 fusion transcript. The double-underlined AG is recognized as a splicing acceptor site. C, schematic representation of breakpoint regions of NUP98 at 11p15 and HOXC11 at 12q13. Exons of NUP98 and HOXC11 are showed as closed and open boxes, respectively. Restriction sites for BglII are indicated by G. Vertical arrows indicate a breakpoint. A horizontal arrow indicates HAL1 LINE repetitive elements.

 
The majority of leukemia genomic breakpoints existed within introns, but were different in each case, therefore allowing the two genes to be spliced together at exon-intron boundaries. The breakpoint of HOXC11 in our patient appeared to have occurred within exon 1, hence the 3' part of exon 1 that created the fusion transcript with NUP98 did not contain a splicing acceptor site, indicating that the 8-bp sequence from just the 5' side of the breakpoint of NUP98 transcribed to the NUP98-HOXC11 fusion transcript as a part of exon 1 of HOXC11. It is very rare for chromosomal breaks to occur at the same point at the genomic level, suggesting that the same NUP98-HOXC11 fusion transcript as that observed in our patient might not be found in other patients. Two similar complex fusion transcripts were observed in t(7;11)(p15;p15). One explanation is that the breakpoint of HOXA9 existed on the 5' side of exon 1 and that the NUP98-HOXA9 fusion transcript was created by a part of exon 1 [(designated as exon 1B by Nakamura et al. (4) ], although genomic analysis revealed that two exons, exon 1A and exon 1B of HOXA9, were found to be a single exon. An alternative is that a single translocation of t(7;11)(p15;p15) in one patient can produce double-chimeric transcripts (both NUP98-HOXA9 and NUP98-HOXA11 or NUP98-HOXA13), of which the genomic breakpoint existed within intron 1 of HOXA11 or HOXA13, not within HOXA9 (9) . These suggested that there may be a particular splicing mechanism in NUP98-HOX fusion transcripts.

The NUP98-HOXC11 fusion transcripts are predicted to encode a protein of 592 amino acids. This fusion protein consists of an NH2-terminal FG repeat motif and a COOH-terminal homeodomain (Fig. 2C)Citation . Both the NH2-terminal FG repeat motif of NUP98 and the COOH-terminal homeodomain of HOXC11 are retained in the NUP98-HOXA9, NUP98-HOXA11, NUP98-HOXA13, NUP98-HOXD13, NUP98-HOXD11, and NUP98-PMX1 fusion proteins (4, 5, 6, 7, 8, 9, 10) . Moreover, mice transplanted with bone marrow cells expressing NUP98-HOXA9 through retroviral transduction develop a myeloproliferative disease and eventually succumb to AML (20) . These findings suggest that NUP98-HOX fusion transcripts exhibit oncogenicity that leads to leukemogenesis.

The expression of HOXC11 was reported to be found in human lymphoid leukemia cell lines, but not in myeloid leukemia cell lines, by Northern blot analysis (21) , although leukemia cells with this NUP98-HOXC11 fusion transcript were diagnosed as AML. To confirm the expression pattern of HOXC11, we performed RT-PCR analysis in 64 leukemia cell lines and 5 EBV-B cell lines. HOXC11 was expressed in 5 of 22 (22.7%) myeloid lineage cell lines, including 2 of 9 (22.2%) AML cell lines, 1 of 6 (16.7%) AMOL cell lines, 0 of 2 AMKL cell lines, and 2 of 5 (40.0%) CML cell lines, and in 2 of 42 (4.8%) lymphoid leukemia cell lines, including 2 of 22 (9.1%) B-precursor ALL and 0 of 10 B-ALL or 10 T-ALL cell lines (Table 1)Citation . Interestingly, two B-precursor ALL cell lines included one cell line with MLL-AF4, and another with TEL-AML1, which had a myeloid marker. Although the frequency of HOXC11 expression was not high in leukemia cell lines, its expression was significantly more frequent in myeloid leukemia cell lines than in lymphoid leukemia cell lines (P = 0.0418), suggesting that the NUP98-HOXC11 fusion protein plays a role in the pathogenesis of myeloid malignancies.


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  		Table 1 Expression of the HOXC11 gene in leukemia and EBV-B cell lines by RT-PCR

 
It was recently reported that several types of NUP98-HOXA and NUP98-HOXD fusions were detected in myeloid malignancies with t(7;11)(p15;p15) (4 , 5 , 9 , 10) and t(2;11)(q31;p15) (6 , 8) , respectively. These findings suggest that other types of NUP98-HOXC11 or other NUP98-HOXC fusions might be formed in other cases with t(11;12)(p15;q13). Further accumulation and analysis of patients with t(11;12)(p15;q13) are needed.


   ACKNOWLEDGMENTS
 
We thank Prof. Seiji Yamaguchi (Department of Pediatrics, Shimane Medical University, Shimane, Japan) for critical comments and Shoko Sohma, Hisae Soga, and Yumiko Taketani for excellent technical assistance. We thank Dr. Takeyuki Sato (Department of Pediatrics, Chiba University School of Medicine, Chiba, Japan) for providing AMKL (CMS and CMY) cell lines, Dr. Kanji Sugita (Department of Pediatrics, Yamanashi University School of Medicine, Yamanashi, Japan) for providing ALL (KOCL-44, KOCL-45, and KOPN-41) and AMOL (KOCL-48) cell lines, and Dr. Yoshinobu Matsuo (Hayashibara Biochemical Laboratories, Inc., Fujisaki Cell Center, Okayama, Japan) for providing varieties of ALL cell lines.


   FOOTNOTES
 
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.

1 Supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan; a Grant-in-Aid for Scientific Research on Priority Areas and Grant-in-Aid for Scientific Research (B) and (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and by the Kawano Medical Foundation. Back

2 To whom requests for reprints should be addressed, at Department of Pediatrics, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-3815-5411, ext. 33452; Fax: 81-3-3816-4108; E-mail: hayashiy-tky{at}umin.ac.jp Back

3 The abbreviations used are: AML, acute myeloid leukemia; RT-PCR, reverse transcription-PCR; ALL, acute lymphoblastic leukemia; FG, phenylalanine-glycine; BMT, bone marrow transplantation; nt, nucleotide(s); AMOL, acute monocytic leukemia; CML, chronic myelogenous leukemia; AMKL, acute megakaryoblastic leukemia; EBV-B, EBV-transformed B lymphocyte; B-ALL, B-cell ALL, T-ALL, T-cell ALL. Back

Received 3/19/02. Accepted 6/25/02.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

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M. Iwasaki, T. Kuwata, Y. Yamazaki, N. A. Jenkins, N. G. Copeland, M. Osato, Y. Ito, E. Kroon, G. Sauvageau, and T. Nakamura
Identification of cooperative genes for NUP98-HOXA9 in myeloid leukemogenesis using a mouse model
Blood, January 15, 2005; 105(2): 784 - 793.
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A. T. Look
Molecular Pathogenesis of MDS
Hematology, January 1, 2005; 2005(1): 156 - 160.
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R. M. Gurevich, P. D. Aplan, and R. K. Humphries
NUP98-Topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation
Blood, August 15, 2004; 104(4): 1127 - 1136.
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N. Pineault, C. Abramovich, H. Ohta, and R. K. Humphries
Differential and Common Leukemogenic Potentials of Multiple NUP98-Hox Fusion Proteins Alone or with Meis1
Mol. Cell. Biol., March 1, 2004; 24(5): 1907 - 1917.
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T. Taketani, T. Taki, K. Sugita, Y. Furuichi, E. Ishii, R. Hanada, M. Tsuchida, K. Sugita, K. Ida, and Y. Hayashi
FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy
Blood, February 1, 2004; 103(3): 1085 - 1088.
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G. Ghannam, A. Takeda, T. Camarata, M. A. Moore, A. Viale, and N. R. Yaseen
The Oncogene Nup98-HOXA9 Induces Gene Transcription in Myeloid Cells
J. Biol. Chem., January 9, 2004; 279(2): 866 - 875.
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G. J. Miller, H. L. Miller, A. van Bokhoven, J. R. Lambert, P. N. Werahera, O. Schirripa, M. S. Lucia, and S. K. Nordeen
Aberrant HOXC Expression Accompanies the Malignant Phenotype in Human Prostate
Cancer Res., September 15, 2003; 63(18): 5879 - 5888.
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I. Lahortiga, J. L. Vizmanos, X. Agirre, I. Vazquez, J. C. Cigudosa, M. J. Larrayoz, F. Sala, A. Gorosquieta, K. Perez-Equiza, M. J. Calasanz, et al.
NUP98 Is Fused to Adducin 3 in a Patient with T-Cell Acute Lymphoblastic Leukemia and Myeloid Markers, with a New Translocation t(10;11)(q25;p15)
Cancer Res., June 15, 2003; 63(12): 3079 - 3083.
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N. Pineault, C. Buske, M. Feuring-Buske, C. Abramovich, P. Rosten, D. E. Hogge, P. D. Aplan, and R. K. Humphries
Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1
Blood, June 1, 2003; 101(11): 4529 - 4538.
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