The HOXD11 Gene Is Fused to the NUP98 Gene in Acute Myeloid Leukemia with T(2;11)(Q31;P15)1

[CANCER RESEARCH 62, 33–37, January 1, 2002] Advances in Brief

The HOXD11 Gene Is Fused to the NUP98 Gene in Acute Myeloid Leukemia with t(2;11)(q31;p15)1

Takeshi Taketani, Tomohiko Taki, Noriko Shibuya, Etsuro Ito, Junichi Kitazawa, Kiminori Terui, 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 Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Aomori 036-8562, Japan [E. I., J. K., K. T.]

Abstract RNA and protein between the nucleus and cytoplasm; it is an essential component of multiple RNA export pathways (12, 13). The nucleoporin gene, NUP98, has been reported to be fused to seven The homeobox genes have a conserved homeodomain sequence partner genes in hematological malignancies with 11p15 translocations. discovered in genes of the Drosophila melanogaster and encode We report here a novel NUP98 partner gene, HOXD11, not HOXD13,in a pediatric patient with de novo AML having t(2;11)(q31;p15), using a transcription factors that act as morphogenetic regulatory molecules cDNA panhandle PCR. The HOXD11 gene is one of the HOXD cluster (14). The homeobox genes act in the patterning of the development of genes and contains 2 exons, encoding a protein of 338 amino acids with a many segmental and axial structures in several organisms (14). The 39 homeodomain. Reverse transcription (RT)-PCR analysis showed that two human homeobox-containing genes (HOX genes) are organized in alternatively spliced 5؅-NUP98 transcripts were fused in frame to the four clusters (HOX-A, B, C, and D). The HOX gene expression in

HOXD11 gene. Both proteins consist of an NH2-terminal phenylalanine- hematopoietic cells varies, depending on differences in the lineage glycine repeat motif of NUP98 and COOH-terminal homeodomain of and maturation of the cells (15). HOXD11. RT-PCR analysis in various leukemic cell lines showed that To our knowledge, only five patients with t(2;11)(q31;p15) have expression of the HOXD11 gene was significantly more frequent in BCR- been reported previously (7, 16–19). These patients were diagnosed .(0.028 ؍ ABL-positive than in BCR-ABL-negative leukemic cell lines (P as having myeloid malignancies, including three with AML (7, 18, 19) Our results revealed that t(2;11)(q31;p15) was not a single chromosomal abnormality and that the NUP98-HOXD fusion genes encode similar and two with myelodysplastic syndrome (MDS; Refs. 16, 17). fusion proteins, which suggests that the NUP98-HOXD11 as well as NUP98-HOXD13 fusion transcripts were found in the three AML NUP98-HOXD13 fusion protein play a role in leukemogenesis through patients with the translocation. We report here a novel partner gene of similar mechanisms. NUP98, HOXD11,inade novo pediatric patient with t(2;11)(q31; p15)-AML. We also report a specific expression pattern of the Introduction HOXD11 and HOXD13 genes.

Chromosomal translocations are associated with specific subtypes Materials and Methods of hematological malignancies (1–3). The AML1 (RUNX1), MLL, MOZ, and TEL (ETV6) genes are found to be fused to a variety of Patients. A 15-year-old boy was diagnosed as having acute myelomono- partner genes in AML3 (1, 2). The NUP98 gene, located on 11p15, cytic leukemia [AMMoL; French-American-British (FAB) classification, M4] was reported to be fused to seven different partner genes, HOXA9 that was cytogenetically characterized as 46, XY, t(2;11)(q31;p15) in all of the (7p15) (4, 5), DDX10 (11q22) (6), HOXD13 (2q31) (7), PMX1 (1q23) 20 bone marrow cells examined. The WBC count at diagnosis was 187,900/␮l (8), RAP1GDS1 (4q21) (9), TOP1 (20q11) (10), and LEDGF (9p22) with 44% leukemic blasts, which expressed CD11b, CD13, CD15, CD33, (11). Among the partner genes of the NUP98 gene, HOXA9, CD36, CD38, CD56, and HLA-DR antigens. A complete remission was achieved 4 months after diagnosis by chemotherapy on the AML-Berlin- HOXD13, and PMX1, are homeobox genes and part of their DNA Frankfurt-Munster 87 protocol. His karyotype was 46, XY in all 20 bone binding homeodomain is fused in frame to a domain encoding the marrow cells. Five months after diagnosis, he underwent a cord blood stem cell NH2-terminal FG repeat of the NUP98 gene (4, 5, 7, 8). transplantation from an unrelated HLA two-locus mismatched donor and has NUP98 is a Mr 98,000 component of NPC located on the nucleo- been in a complete remission for 7 months. Bone marrow leukemic cells were plasmic side of the NPC (12). NUP98 consists of an FG repeat motif, obtained from the patient at diagnosis after informed consent was given. Gle2p-binding-like motif, and ribonucleoprotein-binding motif (12). cDNA Panhandle PCR. To detect the 3Ј unknown gene fused to the 5Ј NUP98 functions as one of several docking NUPs for the transport of NUP98 gene, we adapted the cDNA panhandle PCR strategy with some modification, which was reported as a method to detect MLL fusion partner genes (Ref. 20; Fig. 2A). Total RNA was extracted from the patient’s leukemic Received 4/27/01; accepted 11/5/01. The costs of publication of this article were defrayed in part by the payment of page cells using the acid guanidine thiocyanate-phenol chloroform method (21). charges. This article must therefore be hereby marked advertisement in accordance with Four ␮g of total RNA was reverse-transcribed to first-strand cDNAs using 18 U.S.C. Section 1734 solely to indicate this fact. oligonucleotides with the known NUP98 coding sequence from the predicted 1 Supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor breakpoint region at the 5Ј ends and random hexamers at the 3Ј ends and Welfare of Japan, a Grant-in-Aid for Scientific Research on Priority Areas, and Ј Ј Grant-in-Aid for Scientific Research (B) and (C) from the Ministry of Education, Culture, (5 -CTGGACAGGCATCTTTGTTTGGGAACAACCNNNNNN-3 ), using a Sports, Science and Technology of Japan. This work also was supported by Kawano cDNA synthesis kit (Amersham Pharmacia Biotech, Buckinghamshire, Eng- Medical Foundation. land). To test for the presence of amplifiable RNA, ␤-actin was amplified 2 To whom requests for reprints should be addressed, at Department of Pediatrics, using the same cDNA by RT-PCR. To generate sense second-strand templates Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, ␮ ␮ 113-8655, Japan. Phone: 81-3-3815-5411, extension 33452; Fax: 81-3-3816-4108; E- for panhandle PCR, 2 l of the cDNA solution was added to a 98- l mixture mail: [email protected]. containing 2 units of rTth DNA polymerase, 200 ␮M each: dNTP, 3.3ϫ buffer, 3 The abbreviations used are: AML, acute myeloid leukemia; RT, reverse transcription; MgCl2 1mM (Applied Biosystems, Foster, CA), and 40 pmol of NUP98–1S NUP, nucleoporin; ALL, acute lymphoblastic leukemia; FG, phenylalanine-glycine; NPC, (5Ј-GGGACTCTTGGAACTGGGCTT-3Ј). PCR amplification was performed nuclear pore complex; MNC, mononuclear cell; CML, chronic myelogenous leukemia; AMKL, acute megakaryoblastic leukemia; AMOL, acute monocystic leukemia; EBV-B, with this mixture using a DNA thermal-cycler (Applied Biosystems) under the EBV-transformed B lymphocyte; HOX, homeobox. following conditions: preheating at 94°C for 1 min, 25 cycles of denaturation 33

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2002 American Association for Cancer Research. NUP98-HOXD11 FUSION GENE IN t(2;11)-AML for15sat94°C, and annealing and extension for 10 min at 68°C, with a final extension of 10 min at 72°C. To make intrastrand annealing and polymerase extension, NUP98–1S extension was achieved by denaturing at 94°C for 9 min followed by 1 cycle at 94°C for 1 min and 72°C for 8 min. As a result, stem-loop templates contained the fusion point of the chimeric transcript in the loop. Using NUP98–2S (5Ј-CCTCTTGGTACAGGAGCCTTT-3Ј) between the NUP98 sequence that was complementary to the ligated oligonucleotide and the breakpoint region, RT-PCR was performed with mixtures (50 ␮l) containing 12.5 pmol of NUP98 primer 1 and 2, 200 ␮M each: dNTP and 10ϫ buffer. After initial denaturation at 94°C for 9 min, 40 cycles at 94°C for 1 min, at 55°C for 1 min, and at 72°C for 3 min, were used, followed by a final elongation at 72°C for 7 min. Nested RT-PCR was performed with the same conditions and 1 ␮l of the initial RT-PCR. The primers for nested RT- PCR were NUP98–3S (5Ј-GCAGGATTTGGAACAGCTCTTGGT-3Ј) and NUP98–4S (5Ј-ACTACGACAGCCACTTTGGG-3Ј). Nucleotide Sequencing. PCR products were cloned into the TA cloning Fig. 1. Southern blotting of the NUP98 and HOXD11 genes with EcoRI. Arrows, vector (Ref. 21; Invitrogen, Carlsbad, CA). Nucleotide sequences were deter- rearranged bands of the NUP98 (A) and HOXD11 (B) genes; P, patient’s leukemic cells; C, control EBV-B cell line. mined by the fluorometric method (Dye Terminator Cycle sequencing kit; Applied Biosystems). Southern Blot Analysis. High-molecular-weight DNA was extracted from bone marrow cells of the patients by proteinase K digestion and phenol/ that the NUP98 gene in this patient is not fused to the HOXD13 gene, chloroform extraction (22). Ten ␮g of DNA were digested with EcoRI, but to a novel partner gene. subjected to electrophoresis on 0.7% agarose gels, and transferred to cDNA To isolate the novel partner gene of the NUP98, we performed a probes that were 32P-labeled by the random hexamer method (21). Probes used cDNA panhandle PCR for total RNA from the patient’s leukemic were 837 bp NUP98 cDNA fragments [nucleotide (nt)1213 to 2049; GenBank cells. A cDNA panhandle PCR product of 281 bp was obtained (Fig. accession no. U41815] and 316 bp HOXD11 cDNA fragments (nt 527 to nt 2B), which consisted of a 246-bp unknown sequence fused to the 842; GenBank accession no. XM002543). NUP98 gene. BLAST database searching revealed that the sequence RT-PCR. The same conditions as for the panhandle PCR were used for was homologous to a part of the mouse Hoxd11. We also found that RNA extraction and cDNA synthesis. One ␮l of the cDNA solution was the sequence was identical to the gene that maps to 2q31 on the human amplified by PCR in a total volume of 20 ␮l with 10 mM Tris-HCl (pH 8.3), chromosome (GenBank accession no. AC009336). Therefore, we 50 mM KCl, 1.5 mM MgCl2, 0.001% (w/v) gelatin, 200 mM each dNTP, 2.5 units of Taq polymerase (Applied Biosystems), and 20 pmol of each primer considered that a 246-bp unknown sequence was a part of the human (21). NUP98–5S (5Ј-TTTGGTGCTGTTGGTTCGAC-3Ј) and HOXD11–1AS HOXD11 gene. To isolate the human HOXD11 gene, we performed (5Ј-GGAACCAGATTTTGACTTGCCG-3Ј) were used to confirm the RT-PCR on cDNA from AMOL cell line THP-1 using primers based NUP98-HOXD11 fusion transcripts. HOXD13–1AS (5Ј-ACTCTCTTCTTC- on the mouse Hoxd11, and we cloned a 1017-bp product of the CTCCCTCTTC-3Ј) was used to confirm the NUP98-HOXD13 fusion tran- HOXD11 cDNA (Fig. 2E). The predicted HOXD11 protein consists of scripts. PCR amplification was performed under the following conditions: 338 amino acids with a homeodomain (Fig. 2, D and E). The entire preheating at 94°C for 9 min plus 40 cycles of denaturation for 30 s at 94°C, amino acid sequence exhibits high similarity (93.8%) to the mouse annealing for 30 s at 55°C, and extension for 1 min at 72°C, with a final Hoxd11 protein. Southern blotting with a HOXD11 cDNA probe extension of 7 min at 72°C. Also, expression of the HOXD11 and HOXD13 genes was examined by RT-PCR. The primers used for RT-PCR revealed rearranged bands in the leukemic cells (Fig. 1B). were HOXD11–1S (5Ј-TCCTCTTCTGCCGTTGTAG-3Ј), HOXD11–1AS, RT-PCR analysis using NUP98–5S and HOXD11–1AS revealed HOXD13–1S (5Ј-GACTTCAACTCTCTCGGATGCT-3Ј) and HOXD13– two types of NUP98-HOXD11 in-frame fusion transcripts, one con- 1AS. Amplified products were electrophoresed on a 3% agarose gel, stained taining exon 12 of the NUP98 gene (up to nt 1552) fused to exon 2 of with ethidium bromide, and photographed with a polaroid camera under UV the HOXD11 gene, and the other containing exon 11 of the NUP98 light. gene (up to nt 1411) fused to exon 2 of the HOXD11 gene (Fig. 2, B Cell Lines. To analyze the expression of the HOXD11 and HOXD13 genes, and C). However, no reciprocal fusion transcripts (HOXD11-NUP98) we used 64 cell lines as follows (22): 12 B-precursor ALL cell lines without were detected (Fig. 2B). BCR-ABL transcripts (UTP-L20, P30/OHK, LC4–1, NALM-26, THP-4, We performed RT-PCR analysis in 61 leukemic cell lines, 5 EBV-B THP-5, THP-7, THP-8, RS4;11, KOCL-33, KOCL-44, KOCL-45); 5 B- cell lines and 5 normal MNCs. Expression of the HOXD11 gene was precursor ALL cell lines with BCR-ABL transcripts (BV173, OM9;22, NALM- 20, NALM-24, UTP-2); 10 B-ALL cell lines (BALM-1, BALM-6, BALM-9, found in 4 (80.0%) of 5 CML cell lines, 6 (50.0%) of 12 BCR-ABL- BALM-13, BALM-14, BJAB, DAUDI, RAJI, RAMOS, BAL-KH); 10 T-ALL negative B-precursor ALL cell lines, 3 (60.0%) of 5 BCR-ABL- cell lines (RPMI-8402, MOLT-14, KOPT-KI, THP-6, PEER, JURKAT, positive B-precursor ALL cell lines, 2 (20.0%) of 10 B-ALL cell lines, HSB-2, HPB-ALL, L-SAK, L-SMY); 9 AML cell lines (YNH-1, ML-1, 3 (30.0%) of 10 T-ALL cell lines, 2 (33.3%) of 6 AMOL cell lines, 2 KASUMI-3, KG-1, P39/TSU, inv-3, SN-1, NB4, HEL); 6 AMOL cell lines (22.2%) of 9 AML cell lines, 1 (20.0%) of 5 EBV-B cell lines, and 2 (THP-1, IMS/M1, CTS, P31/FUJ, MOLM-13, KOCL-48); 5 CML cell lines (40.0%) of 5 normal MNCs (Table 1; Fig. 3B). No expression was (MOLM-1, MOLM-7, TS9;22, SS9;22, K-562); 2 AMKL cell lines (CMS, detected in two AMKL cell lines examined. CMY); and 5 EBV-B cell lines derived from normal healthy adult peripheral To compare the expression of the HOXD11 gene with that of the lymphocytes. We also examined MNCs from the peripheral blood of 5 normal HOXD13 gene located on 2q31, expression of the HOXD13 gene was healthy adults. examined by RT-PCR. The HOXD13 gene was expressed in 10 Results and Discussion (41.6%) of 24 myeloid lineage cell lines, including 4 (44.4%) of 9 AML, 3 (50.0%) of 6 AMOL, 2 (100.0%) of 2 AMKL, and 2 (40.0%) Southern blot analysis of DNA from leukemic cells of the patient of 5 CML cell lines by RT-PCR. No expression was found in any using the NUP98 probe showed a rearranged band (Fig. 1A). How- B-ALL cell lines, EBV-B cell lines, or normal MNC, whereas ex- ever, no rearranged bands of the HOXD13 gene were found (data not pression was found in 1 (5.9%) of 17 B-precursor ALL cell lines and shown). No PCR products of the NUP98-HOXD13 chimeric tran- 1 (10.0%) of 10 T-ALL cell lines (Table 1; Fig. 3B). Expression of the scripts were found by RT-PCR (data not shown). Thus, we considered HOXD11 gene was found significantly more frequently than that of 34

Fig. 2. Detection of the novel NUP98 partner gene, the HOXD11 gene. A, schematic representation of primers for a cDNA panhandle PCR strategy and RT-PCR. B, The NUP98-HOXD11 chimeric transcript detected by cDNA panhandle PCR and RT PCR. M, size marker; Lane 1, cDNA panhandle PCR products; Lanes 2, 4, and 5, NUP98-HOXD11 chimeric transcripts detected by RT-PCR; Lane 2, patient; Lane 4, leukemic cell line (NB4); Lane 5, water; Lane 3, patient (HOXD11-NUP98 chimeric transcripts). C, sequencing of two NUP98-HOXD11 chimeric transcripts. Arrows, the fusion point. D, structure of the predicted NUP98, HOXD11, and NUP98-HOXD11 fusion proteins. GLEBS, Gle2p-binding like motif; HD, homeodomain. E, cDNA sequence (1017 bp) of human HOXD11 with predicted amino acid sequence. Underlined, the homeodomain. Vertical arrow, the position of the t(2;11) breakpoint. the HOXD13 gene in ALL cell lines and BCR-ABL-positive leukemic HOXD11, a human homologue of mouse Hoxd11,isahomeobox cell lines (P ϭ 0.0007 and P ϭ 0.038, respectively). gene. The function of the HOXD11 gene in hematopoiesis remains The HOXD13 gene has been identified as a fusion partner of the unclear, although other HOX genes, such as the HOXC cluster and NUP98 gene in t(2;11)(q31;p15)-AML (7). In the present study, we HOXA9, were reported to be important in hematopoiesis (15, 24). isolated a novel chimeric transcript, NUP98-HOXD11,inade novo The Hoxd11 gene contributes to the development of front legs in pediatric patient with AML (M4) having t(2;11)(q31;p15), which was mice (25). the same translocation breakpoint as NUP98-HOXD13. Recent molecular analysis has shown that different genes in the same chromo- Table 1 Expression of the HOXD11 and HOXD13 genes in leukemia and EBV-B cell somal region were identified as fusion partners of MLL, such as lines and normal lymphocytes by RT-PCR MLL-ELL, MLL-ENL, and MLL-EEN in t(11;19)(q23;p13) (2). Our Expression Classifications of Total no. result suggests that it is difficult to predict the fusion partner of the cell lines examined HOXD11 HOXD13 NUP98 gene in t(2;11)(q31;p15) only by cytogenetics. ALL 37 14 2 Two NUP98-HOXD11 fusion transcripts are predicted to encode a B-precursor 12 6 1 protein of 499 amino acids and 547 amino acids, respectively. Both Ph1a 530 B1020 proteins are caused by the alternative splicing consist of an NH2- T1031 terminal FG repeat motif and COOH-terminal homeodomain. The AML 17 4 9 difference between these chimeric proteins is attributable to the num- AML 9 2 4 AMOL 6 2 3 ber of FG peptide repeats. Both the NH2-terminal FG repeat motif and COOH-terminal homeodomain are retained in the NUP98-HOXA9, AMKL 2 0 2 NUP98-HOXD13, and NUP98-PMX1 fusion proteins. Mice trans- CML 5 4 2 planted with bone marrow cells expressing NUP98-HOXA9 through Normal cells 10 3 0 EBV-B 5 1 0 retroviral transduction acquire a myeloproliferative disease and even- Normal 5 2 0 tually succumb to AML (23). This suggests that NUP98-HOXD11 a Ph1, B-precursor ALL with BCR-ABL transcripts; Normal, peripheral blood mono- could use a similar mechanism that leads to leukemogenesis. nuclear cells from healthy adults. 35

Fig. 3. A, structure of the HOXD11, HOXD12, and HOXD13 genes. Arrows, primers used for RT-PCR. B, expression of the HOXD11 and HOXD13 genes in varieties of leukemic cell lines and normal peripheral blood lymphocytes detected by RT-PCR. Lanes 1–3, B precursor (B-pre) ALL cell lines; Lanes 4–6, B-ALL cell lines; Lanes 7–9, T-ALL cell lines; Lanes 10–12, AML cell lines; Lanes 13–15, AMOL cell lines; Lanes 16–17, AMKL cell lines; Lanes 18–20, CML cell lines; Lanes 21–23, EBV-B cell lines; Lanes 24–26, normal peripheral MNCs.

Expression of the HOX genes in hematopoietic cell lines results in cine, Chiba, Japan) for providing AMKL (CMS, CMY) cell lines, Dr. Kanji differences in lineage commitment and maturation of these cells (15); Sugita (Department of Pediatrics, Yamanashi University School of Medicine, for example, expression of the HOXA10 gene was restricted to my- Yamanashi, Japan) for providing ALL (KOCL-33, 44, 45) cell lines and elomonocytic cell lines (26) and expression of the HOXC4 gene was AMOL (KOCL-48) cell lines, and Dr. Yoshinobu Matsuo (Hayashibara Bio- predominant in lymphoid cell lines (27). In HOXD cluster genes, it chemical Laboratories, Inc., Fujisaki Cell Center, Okayama, Japan) for pro- was reported that expression of the HOXD3 gene was found in HEL viding varieties of ALL cell lines. We also thank Drs. Yasuhito Arai and Misao and K562 but not in HL-60 (28), whereas expression of the HOXD13 Ohki for their critical information on the NUP98 gene. gene was found in HEL, Kasumi-1, and MOLT-4 but not in U937 (18). Our study revealed that expression of the HOXD11 gene was References significantly higher in BCR-ABL-positive leukemic cell lines than in 1. Rowley, J. D. The critical role of chromosome translocations in human leukemias. BCR-ABL-negative leukemic cell lines (P ϭ 0.028). The reason for Ann. Rev. Genet., 32: 495–519, 1998. 2. Hayashi, Y. The molecular genetics of recurring chromosome abnormalities in acute high expression of the HOXD11 gene in BCR-ABL-positive leukemic myeloid leukemia. Semin. Hematol., 37: 368–380, 2000. cell lines is unclear. Expression of the HOXD11 gene was found more 3. Ferrando, A. A., and Look, A. T. Clinical implications of recurring chromosomal and frequently in BCR-ABL-negative B-precursor ALL cell lines and associated molecular abnormalities in acute lymphoblastic leukemia. Semin. Hema- tol., 37: 381–395, 2000. CML cell lines than in other cell lines, but these differences were not 4. Borrow, J., Shearman, A. M., Stanton, V. P. Jr., Becher, R., Collins, T., Williams, significant statistically. Notably, expression of the HOXD13 gene was A. J., Dube, I., Katz, F., Kwong, Y. L., Morris, C., Ohyashiki, K., Toyama, K., significantly higher in myeloid cell lines than in lymphoid cell lines Rowley, J., and Housman, D. E. The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. (P Ͻ 0.0001). Overexpression of Hoxb8 with interleukin-3, Hoxa10, Nat. Genet., 12: 159–167, 1996. Hoxb3, and Hoxa9, with Meis1 in murine hematopoietic cells was 5. Nakamura, T., Largaespada, D. A., Lee, M. P., Johnson, L. 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Blood, 89: 3936–3944, 1997. HOXD13 but also the NUP98-HOXD11 fusion gene. Although ex- 7. Raza-Egilmez, S. Z., Jani-Sait, S. N., Grossi, M., Higgins, M. J., Shows, T. B., and Aplan, P. D. NUP98-HOXD13 gene fusion in therapy-related acute myelogenous pression of the HOXD11 and HOXD13 genes in leukemic cell lines leukemia. Cancer Res., 58: 4269–4273, 1998. was different, the NUP98-HOXD fusion genes encode similar fusion 8. Nakamura, T., Yamazaki, Y., Hatano, Y., and Miura, I. NUP98 is fused to PMX1 proteins, suggesting that the NUP98-HOXD11 as well as NUP98- homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15). Blood, 94: 741–747, 1999. HOXD13 fusion protein play a role in leukemogenesis through similar 9. Hussey, D. J., Nicola, M., Moore, S., Peters, G. B., and Dobrovic, A. The (4;11)(q21; mechanism. 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Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2002 American Association for Cancer Research. The HOXD11 Gene Is Fused to the NUP98 Gene in Acute Myeloid Leukemia with t(2;11)(q31;p15)

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

Cancer Res 2002;62:33-37.

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