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

[CANCER RESEARCH 62, 4571–4574, August 15, 2002] 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 related AML.3 We identified a novel partner gene of NUP98, HOXC11,inade novo pediatric patient with t(11;12)(p15;q13)-AML The NUP98 gene has been reported to be fused to 11 partner genes in and determined genomic breakpoints between NUP98 and HOXC11. hematological malignancies with 11p15 translocations. Among NUP98 We also report a specific expression pattern of the HOXC11 genes in fusion partner genes, HOXA and HOXD clusters have been reported thus various leukemia cell lines. 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 Materials and Methods NUP98 was located within a LINE repetitive sequence (HAL1) in intron 12, and the breakpoint of HOXC11 was located within exon 1, resulting in Patients. A 14-year-old boy was diagnosed with AML (French-American- a NUP98-HOXC11 in-frame fusion transcript containing exon 12 of British classification M1), which was cytogenetically characterized as 46, XY, NUP98 fused to a part of exon 1 of HOXC11 with an 8-bp insertion derived t(11;12)(p15;q13) in all 20 bone marrow cells examined. The WBC count at ␮ ,from the intron sequence just 5؅ of the breakpoint of NUP98. The NUP98- diagnosis was 12,500/ l with 87% leukemic blasts, which expressed CD13 HOXC11 fusion protein consists of the NH -terminal phenylalanine- CD33, and HLA-DR antigens. Complete remission was achieved 1 month after 2 diagnosis by chemotherapy on the ANLL-91 protocol (16). His karyotype glycine repeat motif of NUP98 and the COOH-terminal homeodomain of showed 46, XY in all 20 bone marrow cells in remission. Nine months after HOXC11. Although the frequency of HOXC11 expression was not high in diagnosis, he underwent an allogeneic BMT from a HLA-matched sibling leukemia cell lines, its expression was significantly more frequent in donor and was in complete remission for 6 months. A relapse occurred in the myeloid than lymphoid leukemia cell lines. These data suggest that the bone marrow 7 months after BMT, and he died of progressive disease 10 NUP98-HOXC11 fusion protein plays a role in the pathogenesis of mye- months after BMT. Leukemic cells from bone marrow were obtained from the loid malignancies. patient at diagnosis after informed consent was given. Southern Blot Analysis. High molecular weight DNA was extracted from Introduction bone marrow cells of the patient by proteinase K digestion and phenol/ ␮ A great number of recurrent chromosomal translocations are related chloroform extraction (17). Ten g of DNA were digested with BamHI, subjected to electrophoresis on 0.7% agarose gels, and transferred to cDNA to leukemia and myelodysplastic syndrome (1, 2). Remarkable pro- probes labeled with 32P by the random hexamer method (17). The probes used gress in molecular genetics has brought a better understanding of were an 837-bp NUP98 cDNA fragment (nt 1213–2049; GenBank accession several genes involved in these translocations. Recently, leukemia and number U41815) and a 333-bp HOXC11 cDNA fragment (nt 503–835; Gen- myelodysplastic syndrome with chromosome 11p15 translocations Bank accession number AJ000041). have been reported to involve the NUP98 gene (2, 3). To date, 11 RT-PCR for Identification of a Novel Partner Gene of NUP98. To different partner genes fused to NUP98 have been identified (2–10). detect the 3Ј unknown gene fused to the 5Ј NUP98 gene, we adapted a RT-PCR method. Total RNA was extracted from the leukemia cells of the patient using NUP98 is a Mr 98,000 component of the nuclear pore complex located on its nucleoplasmic side, and it selectively transports RNA the acid guanidinium thiocyanate-phenol chloroform method (17). Total RNA ␮ and protein between the nucleus and cytoplasm (11). The HOX genes (4 g) was reverse-transcribed to cDNA, using a cDNA synthesis kit (Amer- sham Pharmacia Biotech, Buckinghamshire, England; Ref. 17). To test for the are transcriptional factors for which the regulation of embryonic presence of amplifiable RNA, ␤-actin was amplified using the same cDNA by morphological development is required (12). Human class I HOX RT-PCR. One ␮l of the cDNA solution was amplified by PCR in a total genes belonging to four different clusters (A, B, C, and D) are located ␮ volume of 20 l with 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, on chromosomes 7, 17, 12 ,and 2, respectively. Among NUP98 fusion 0.001% (w/v) gelatin, 5% DMSO, 200 mM of each deoxyribonucleotide partner genes, five class I HOX genes, HOXA9 (7p15; Refs. 4 and 5), triphosphate, 2.5 units of Taq polymerase (Applied Biosystems, Foster, CA), HOXA11 (7p15; Ref. 9), HOXA13 (7p15; Refs. 9 and 10), HOXD13 and 10 pmol of each primer. The sense primer used for RT-PCR was NUP98- (2q31; Ref. 6), and HOXD11 (2q31; Ref. 8), have been reported thus 1507S (5Ј-ACTACGACAGCCACTTTGGG-3Ј), and the antisense primer was far. However, no HOXC or HOXB genes have been reported as yet. HOXC11-791AS (5Ј-TGCAGCCGCTTCTCTTTGTT-3Ј). Other HOXC clus- Three patients with t(11;12)(p15;q13) have been reported previ- ter genes (HOXC9, HOXC10, HOXC12, and HOXC13) were also used as ously (13–15). All these patients were diagnosed as having therapy- 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, Received 3/19/02; accepted 6/25/02. and 72°C for 1 min; followed by a final elongation at 72°C for 7 min. 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 Long PCR. To detect genomic breakpoints between NUP98 and HOXC11, 18 U.S.C. Section 1734 solely to indicate this fact. we adopted a long PCR method. One hundred ng of the DNA were amplified 1 Supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, by PCR in a 50-␮l (total volume) mixture containing 2.5 units of TaKaRaLA 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. 3 The abbreviations used are: AML, acute myeloid leukemia; RT-PCR, reverse tran- 2 To whom requests for reprints should be addressed, at Department of Pediatrics, scription-PCR; ALL, acute lymphoblastic leukemia; FG, phenylalanine-glycine; BMT, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo bone marrow transplantation; nt, nucleotide(s); AMOL, acute monocytic leukemia; CML, 113-8655, Japan. Phone: 81-3-3815-5411, ext. 33452; Fax: 81-3-3816-4108; E-mail: chronic myelogenous leukemia; AMKL, acute megakaryoblastic leukemia; EBV-B, EBV- [email protected]. transformed B lymphocyte; B-ALL, B-cell ALL, T-ALL, T-cell ALL. 4571

(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

Southern blot analysis of DNA from leukemia cells of the patient

Fig. 1. Southern blotting of the NUP98 and HOXC11 genes with BglII. Arrows indicate using the NUP98 probe showed a rearranged band (Fig. 1A). Thus, we a rearranged band of the NUP98 (A) and HOXC11 (B) genes. P, patient; C, control. 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 Taq polymerase, 400 ␮M of each deoxyribonucleotide triphosphate, 10ϫ LA (7p15; Ref. 9), and HOXA13 (7p15; Refs. 9 and 10) in AML with 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 t(7;11)(p15;p15) and HOXD11 (2q31; Ref. 8) and HOXD13 (2q31; NUP98-1507S, and the antisense primer was HOXC11-616AS (5Ј-TGTTCTC- Ref. 6) in AML with t(2;11)(q31;p15). Human class I HOXC genes CTCCTCAGCCTC-3Ј). For the reciprocal HOXC11-NUP98 fusion gene, the were located on chromosome 12q13. Therefore, we considered that a sense primer was HOXC11-459S, and the antisense primer was NUP98-int12- novel partner gene fused to NUP98 in t(11;12)(p15;q13) was one of 475AS (5Ј-AGCGCGAGACTCCTTTTCA-3Ј). PCR amplification was per- the HOXC cluster genes. To isolate the novel partner gene of NUP98, formed under the following conditions: preheating at 95°C for 1 min; 35 cycles we performed RT-PCR for total RNA from the patient’s leukemia of denaturation for 30 s at 95°C and annealing and extension for 3 min cells. Using several antisense primers based on the HOXC cluster (increments of 15 s every cycle) at 68°C; with a final extension of 10 min at genes (HOXC9, HOXC10, HOXC11, HOXC12, and HOXC13), we 72°C. obtained an RT-PCR product of 294 bp when NUP98-1507S and Nucleotide Sequencing. PCR products were cloned into the TOPO TA cloning vector (Invitrogen, Carlsbad, CA). The nt sequences were determined HOXC11-791AS were used (Fig. 2A). Sequence analysis showed that by the fluorometric method (Dye Terminator Cycle Sequencing Kit; Applied the RT-PCR product was an in-frame fusion transcript of NUP98- Biosystems; Ref. 17). HOXC11 containing exon 12 of the NUP98 gene (up to nt 1552) fused RT-PCR for Examination of HOXC11 Gene Expression. To analyze the to part of exon 1 of HOXC11 with an 8-bp insertion that existed within expression pattern of the HOXC11 gene in leukemia cell lines, RT-PCR was the intron 12 sequence of NUP98 (Fig. 2B). No reciprocal fusion performed. We used 69 cell lines as follows (8, 10): (a) 22 B-precursor ALL transcript (HOXC11-NUP98) was detected (Fig. 2A). Southern blot- cell lines (UTP-L20, P30/OHK, LAZ-221, LC4-1, NALM-26, THP-4, THP-5, ting with a HOXC11 cDNA probe revealed a rearranged band in these THP-7, THP-8, RS4;11, KOCL-44, KOCL-45, BV173, OM9;22, NALM-20, leukemic cells (Fig. 1B). NALM-24, UTP-2, UTP-L5, REH, MV4;11, HAL-01, and KOPN-41); (b)10 We next cloned the genomic breakpoints of NUP98 and HOXC11. 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 Because the NUP98-HOXC11 fusion transcript contains exon 12 and (RPMI-8402, MOLT-14, KOPT-KI, THP-6, PEER, JURKAT, HSB-2, HPB- a part of intron 12 of NUP98 fused to part of exon 1 of HOXC11,we ALL, L-SAK, and L-SMY); (d) 9 AML cell lines (YNH-1, ML-1, KASUMI-3, supposed that the genomic breakpoints lay within intron 12 of NUP98 KG-1, P39/TSU, inv-3, SN-1, NB4, and HEL); (e) 6 AMOL cell lines (THP-1, and the 5Ј side of HOXC11. Thus, we performed long PCR for DNA IMS/M1, CTS, P31/FUJ, MOLM-13, and KOCL-48); (f) 5 CML cell lines from the patient’s leukemic cells to clone the genomic breakpoints

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.

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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2002 American Association for Cancer Research. NUP98-HOXC11 FUSION GENE IN t(11;12) AML and obtained PCR products of 440 bp using primers NUP98-1507S HOXA9 fusion transcript was created by a part of exon 1 [(designated and HOXC11-616AS and 240 bp using primers HOXC11-459S and as exon 1B by Nakamura et al. (4)], although genomic analysis NUP98-int12-475AS (Fig. 3, A and B). The 8-bp inserted sequence revealed that two exons, exon 1A and exon 1B of HOXA9, were found from the NUP98 intron existed just on the 5Ј side of the breakpoint to be a single exon. An alternative is that a single translocation of (Fig. 3B). We considered that derivative chromosome 11 recognized t(7;11)(p15;p15) in one patient can produce double-chimeric tran- an AG site before the 8-bp sequence derived from intron 12 of NUP98 scripts (both NUP98-HOXA9 and NUP98-HOXA11 or NUP98- that formed a part of the NUP98-HOXC11 fusion transcripts as a HOXA13), of which the genomic breakpoint existed within intron 1 of splicing acceptor site (Fig. 3B). The breakpoints at 11p15 and 12q13 HOXA11 or HOXA13, not within HOXA9 (9). These suggested that were located within a LINE repetitive sequence (HAL1) in intron 12 there may be a particular splicing mechanism in NUP98-HOX fusion of NUP98 and within exon 1 of HOXC11, respectively (Fig. 3C). transcripts. Although microduplications were found at the genomic breakpoints of The NUP98-HOXC11 fusion transcripts are predicted to encode a both t(2;11)(q31;p15) (18) and, t(11;20)(p15;q11) (19), there was no protein of 592 amino acids. This fusion protein consists of an NH2- microduplication, topoisomerase II consensus sequence, purine/ terminal FG repeat motif and a COOH-terminal homeodomain (Fig. pyrimidine repeat region, Alu repeats, translin consensus sequence, or 2C). Both the NH2-terminal FG repeat motif of NUP98 and the heptamer/nonamer sequences at or near the breakpoints (Fig. 3B). The COOH-terminal homeodomain of HOXC11 are retained in the genomic breakpoints in NUP98-HOX fusion genes were clustered on NUP98-HOXA9, NUP98-HOXA11, NUP98-HOXA13, NUP98- intron 12 of NUP98 (19). Repeat elements were interspersed in about HOXD13, NUP98-HOXD11, and NUP98-PMX1 fusion proteins (4– 50% of intron 12. These suggested that occurrence of the NUP98- 10). Moreover, mice transplanted with bone marrow cells expressing HOX fusion genes may be associated with repetitive elements of NUP98-HOXA9 through retroviral transduction develop a myelopro- NUP98. liferative disease and eventually succumb to AML (20). These find- The majority of leukemia genomic breakpoints existed within in- ings suggest that NUP98-HOX fusion transcripts exhibit oncogenicity trons, but were different in each case, therefore allowing the two that leads to leukemogenesis. genes to be spliced together at exon-intron boundaries. The breakpoint The expression of HOXC11 was reported to be found in human of HOXC11 in our patient appeared to have occurred within exon 1, lymphoid leukemia cell lines, but not in myeloid leukemia cell lines, hence the 3Ј part of exon 1 that created the fusion transcript with by Northern blot analysis (21), although leukemia cells with this NUP98 did not contain a splicing acceptor site, indicating that the NUP98-HOXC11 fusion transcript were diagnosed as AML. To con- 8-bp sequence from just the 5Ј side of the breakpoint of NUP98 firm the expression pattern of HOXC11, we performed RT-PCR transcribed to the NUP98-HOXC11 fusion transcript as a part of exon analysis in 64 leukemia cell lines and 5 EBV-B cell lines. HOXC11 1ofHOXC11. It is very rare for chromosomal breaks to occur at the was expressed in 5 of 22 (22.7%) myeloid lineage cell lines, including same point at the genomic level, suggesting that the same NUP98- 2 of 9 (22.2%) AML cell lines, 1 of 6 (16.7%) AMOL cell lines, 0 of HOXC11 fusion transcript as that observed in our patient might not be 2 AMKL cell lines, and 2 of 5 (40.0%) CML cell lines, and in 2 of 42 found in other patients. Two similar complex fusion transcripts were (4.8%) lymphoid leukemia cell lines, including 2 of 22 (9.1%) B- observed in t(7;11)(p15;p15). One explanation is that the breakpoint precursor ALL and 0 of 10 B-ALL or 10 T-ALL cell lines (Table 1). of HOXA9 existed on the 5Ј side of exon 1 and that the NUP98- Interestingly, two B-precursor ALL cell lines included one cell line

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.

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Table 1 Expression of the HOXC11 gene in leukemia and EBV-B cell lines by RT-PCR Copeland, N. G., and Shaughnessy, J. D., Jr. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid Classifications Total no. Expression of leukaemia. Nat. Genet., 12: 154–158, 1996. of cell lines examined HOXC11 5. Borrow, J., Shearman, A. M., Stanton, V. P., Jr., Becher, R., Collins, T., Williams, ALL 42 2 A. J., Dube, I., Katz, F., Kwong, Y. L., Morris, C., Ohyashiki, K., Toyama, K., B-precursor 22 2 Rowley, J., and Housman, D. E. The t(7;11)(p15;p15) translocation in acute myeloid B100 leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. T100 Nat. Genet., 12: 159–167, 1996. P ϭ 0.0418 6. Raza-Egilmez, S. Z., Jani-Sait, S. N., Grossi, M., Higgins, M. J., Shows, T. B., and AML 17 3 Aplan, P. D. NUP98-HOXD13 gene fusion in therapy-related acute myelogenous AML 9 2 leukemia. Cancer Res., 58: 4269–4273, 1998. AMOL 6 1 7. Ahuja, H. G., Felix, C. A., and Aplan, P. D. The t(11;20)(p15;q11) chromosomal AMKL 2 0 translocation associated with therapy-related myelodysplastic syndrome results in an CML 5 2 NUP98-TOP1 fusion. Blood, 94: 3258–3261, 1999. EBV-B 5 0 8. Taketani, T., Taki, T., Shibuya, N., Ito E., Kitazawa, J., Terui, K., and Hayashi, Y. The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15). Cancer Res., 62: 33–37, 2002. 9. Fujino, T., Suzuki, A., Ito, Y., Ohyashiki, K., Hatano, Y., Miura, I., and Nakamura, with MLL-AF4, and another with TEL-AML1, which had a myeloid T. Single-translocation and double-chimeric transcripts: detection of NUP98-HOXA9 marker. Although the frequency of HOXC11 expression was not high in myeloid leukemias with HOXA11 or HOXA13 breaks of the chromosomal in leukemia cell lines, its expression was significantly more frequent translocation t(7;11)(p15;p15). Blood, 99: 1428–1433, 2002. 10. Taketani, T., Taki, T., Ono, R., Kobayashi, Y., Ida, K., and Hayashi, Y. The in myeloid leukemia cell lines than in lymphoid leukemia cell lines t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with (P ϭ 0.0418), suggesting that the NUP98-HOXC11 fusion protein a HOXA cluster gene, HOXA13, but not HOXA9. Genes Chromosomes Cancer, 34: 437–443, 2002. plays a role in the pathogenesis of myeloid malignancies. 11. Radu, A., Moore, M. S., and Blobel, G. The peptide repeat domain of nucleoporin It was recently reported that several types of NUP98-HOXA and Nup98 functions as a docking site in transport across the nuclear pore complex. Cell, NUP98-HOXD fusions were detected in myeloid malignancies with 81: 215–222, 1995. 12. McGinnis, W., and Krumlauf, R. Homeobox genes and axial patterning. Cell, 68: t(7;11)(p15;p15) (4, 5, 9, 10) and t(2;11)(q31;p15) (6, 8), respectively. 283–302, 1992. These findings suggest that other types of NUP98-HOXC11 or other 13. Nishiyama, M., Arai, Y., Tsunematsu, Y., Kobayashi, H., Asami, K., Yabe, M., Kato, NUP98-HOXC fusions might be formed in other cases with t(11; S., Oda, M., Eguchi, H., Ohki, M., and Kaneko, Y. 11p15 translocations involving the NUP98 gene in childhood therapy-related acute myeloid leukemia/myelodysplastic 12)(p15;q13). Further accumulation and analysis of patients with syndrome. Genes Chromosomes Cancer, 26: 215–220, 1999. t(11;12)(p15;q13) are needed. 14. Roulston, D., Espinosa, R., III, Nucifora, G., Larson, R. A., Le Beau, M. M., and Rowley, J. D. CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy. Blood, 92: 2879–2885, 1998. Acknowledgments 15. Wong, K. F., Kwong, Y. L., and So, C. C. De novo AML with trilineage myelodys- plasia and a novel t(11;12)(p15;q13). Cancer Genet. Cytogenet., 100: 49–51, 1998. We thank Prof. Seiji Yamaguchi (Department of Pediatrics, Shimane Med- 16. Kawasaki, H., Isoyama, K., Eguchi, M., Hibi, S., Kinukawa, N., Kosaka, Y., Oda, T., ical University, Shimane, Japan) for critical comments and Shoko Sohma, Oda, M., Nishimura, S., Imaizumi, M., Okamura, T., Hongo, T., Okawa, H., Hisae Soga, and Yumiko Taketani for excellent technical assistance. We thank Mizutani, S., Hayashi, Y., Tsukimoto, I., Kamada, N., and Ishii, E. Superior outcome of infant acute myeloid leukemia with intensive chemotherapy: results of Dr. Takeyuki Sato (Department of Pediatrics, Chiba University School of the Japan Infant Leukemia Study Group. Blood, 98: 3589–3594, 2001. Medicine, Chiba, Japan) for providing AMKL (CMS and CMY) cell lines, Dr. 17. Taki, T., Kano, H., Taniwaki, M., Sako, M., Yanagisawa, M., and Hayashi, Y. Kanji Sugita (Department of Pediatrics, Yamanashi University School of AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute Medicine, Yamanashi, Japan) for providing ALL (KOCL-44, KOCL-45, and lymphoblastic leukemia with ins(5;11)(q31;q13q23). Proc. Natl. Acad. Sci. USA, 96: 14535–14540, 1999. KOPN-41) and AMOL (KOCL-48) cell lines, and Dr. Yoshinobu Matsuo 18. Arai, Y., Kyo, T., Miwa, H., Arai, K., Kamada, N., Kita, K., and Ohki, M. Hetero- (Hayashibara Biochemical Laboratories, Inc., Fujisaki Cell Center, Okayama, genous fusion transcripts involving the NUP98 gene and HOXD13 gene activation in Japan) for providing varieties of ALL cell lines. a case of acute myeloid leukemia with the t(2;11)(q31;p15) translocation. Leukemia (Baltimore), 14: 1621–1629, 2000. References 19. Ahuja, H. G., Felix, C. A., and Aplan, P. D. Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations. Genes Chromosomes 1. Rowley, J. D. The critical role of chromosome translocations in human leukemias. Cancer, 29: 96–105, 2000. Annu. Rev. Genet., 32: 495–519, 1998. 20. Kroon, E., Thorsteinsdottir, U., Mayotte, N., Nakamura, T., and Sauvageau, G. 2. Hayashi, Y. The molecular genetics of recurring chromosome abnormalities in acute NUP98-HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemia. Semin. Hematol., 37: 368–380, 2000. myeloid leukemias in mice. EMBO J., 20: 350–361, 2001. 3. Lam, D. H., and Aplan, P. D. NUP98 gene fusions in hematologic malignancies. 21. Lawrence, H. J., Stage, K. M., Mathews, C. H., Detmer, K., Scibienski, R., Leukemia (Baltimore), 15: 1689–1695, 2001. MacKenzie, M., Migliaccio, E., Boncinelli, E., and Largman, C. Expression of 4. Nakamura, T., Largaespada, D. A., Lee, M. P., Johnson, L. A., Ohyashiki, K., HOXC homeobox genes in lymphoid cells. Cell Growth Differ., 4: 665– 669, Toyama, K., Chen, S. J., Willman, C. L., Chen, I. M., Feinberg, A. P., Jenkins, N. A., 1993.

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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2002 American Association for Cancer Research. 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)

Takeshi Taketani, Tomohiko Taki, Noriko Shibuya, et al.

Cancer Res 2002;62:4571-4574.

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