伴t（3;11）（q29q13;p15）的急性杂合性白血病融合基因克隆和功能研究
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摘要
目的和意义
白血病是严重危害人类健康的造血系统恶性疾病,常伴有非随机的细胞遗传学异常,其中最常见的是染色体易位。在急性白血病中约65%的患者伴有特征性的染色体易位,染色体易位的受累基因大多为编码转录因子或受体的酪氨酸激酶基因,编码的融合蛋白干扰细胞增殖、凋亡和分化的正常调控途径,在恶性血液病发病机制中起着重要作用。因此,检测恶性血液病非随机的染色体异常,分离染色体异常受累基因,并进一步研究这些基因的功能及其与恶性血液病发生、发展的关系,对理解恶性血液病的发病机制,寻找有效的诊断标志和治疗方法都具有重要意义。近年来,与染色体11p15异常相关的恶性血液病病例不断增多,至今已发现17种与恶性血液病相关的染色体11p15异常,其中15种染色体易位的靶基因均为位于11p15的NUP98基因。本课题旨在通过对一例伴t(3;11)(q29q13;p15)的急性杂合性白血病的研究,定位克隆t(3;11)(q29q13;p15)染色体易位的受累基因,并对NUP98的伙伴基因及形成的融合基因进行功能初探,以深化我们对NUP98相关融合基因致白血病的发生、发展的认识,从而有助于指导白血病的诊断、预后评估和治疗。
方法
我们对一例伴t(3;11)(q29q13;p15)的原发性急性杂合性白血病进行了深入研究,充分利用当前人类基因组研究所取得的大量信息,采取了定位候选基因克隆策略(positional candidate gene approaches),定位克隆t(3;11)(q29q13;p15)染色体易位的受累基因,进而对NUP98相关融合蛋白的致白血病机制进行了初步的研究。
第一部分:首先通过常规的分子-细胞遗传学方法检测出t(3;11)( q13;p15)染色体易位,并将11号染色体上的断裂点初步定位于11p15的NUP98基因3’端;接着通过cDNA末端快速扩增技术(Rapid Amplification of cDNA Ends, RACE)发现了位于3q29的NUP98伙伴基因NRG(因当时GeneBank无此基因的详细信息,我们姑且命名为NUP98 Related Gene);为了解释RACE结果与核型检测不符之处,我们选取了位于3q21和位于3q29的两个BAC克隆来分析3号染色体复杂异常情
Objective
Leukemia is a kind of malignant tumor of hematopoietic system doing severely harm to human health, always with non-random cytogenetic abnormalities, among which the most frequency is chromosomal translocation. It can be seen in 65% acute leukemia patients. Mostly targed genes of chromosomal translocation are transcriptional factor or trosine-protein kinase, resulting in dysregulative pathwalys of cell proliferation, apoptosis, differentiation and playing an important role in leukemogenesis. Therefore, detection of the recurrent chromosomal translocations, molecular cloning and functional study of the involved genes will shed light on deciphering the molecular mechanisms of leukemogenesis, provide diagnostic markers and allow the development of new therapeutic strategies. In recent years, chromosome aberration involving 11p15 has been reported increasingly. To date at least 17 kinds have been identified. Almost all 11p15 translocations targed the NUP98 gene located at chromosome 11p15. Our work is to provide considerable insight into the mechanisms of NUP98-related fusion genes in leukemia through molecular cloning and functional study of the fusion genes by the chromosome translocation t(3;11)(q29q13;p15) in a hybrid acute leukemia patient Furthermore,it will help to diagnose, guide risk-directed therapy for leukemia.
Methods
We investigated an adult patient with the chromosome translocation t(3;11)(q29q13;p15) in de novo hybrid acute leukemia. With positional candidate gene approaches, we characterized the genes involved in that translocation and subsequently studied the function of the fusion protein in leukemogenic mechanism.
Part I: Firstly, through molecular genetic-cytogenetics, we identified a new chromosomal translocation t(3;11)( q13;p15) and located chromosome breakpoint at the NUP98 gene at 11p15. Using Rapid Amplification of cDNA Ends (RACE), we
白血病是严重危害人类健康的造血系统恶性疾病,常伴有非随机的细胞遗传学异常,其中最常见的是染色体易位。在急性白血病中约65%的患者伴有特征性的染色体易位,染色体易位的受累基因大多为编码转录因子或受体的酪氨酸激酶基因,编码的融合蛋白干扰细胞增殖、凋亡和分化的正常调控途径,在恶性血液病发病机制中起着重要作用。因此,检测恶性血液病非随机的染色体异常,分离染色体异常受累基因,并进一步研究这些基因的功能及其与恶性血液病发生、发展的关系,对理解恶性血液病的发病机制,寻找有效的诊断标志和治疗方法都具有重要意义。近年来,与染色体11p15异常相关的恶性血液病病例不断增多,至今已发现17种与恶性血液病相关的染色体11p15异常,其中15种染色体易位的靶基因均为位于11p15的NUP98基因。本课题旨在通过对一例伴t(3;11)(q29q13;p15)的急性杂合性白血病的研究,定位克隆t(3;11)(q29q13;p15)染色体易位的受累基因,并对NUP98的伙伴基因及形成的融合基因进行功能初探,以深化我们对NUP98相关融合基因致白血病的发生、发展的认识,从而有助于指导白血病的诊断、预后评估和治疗。
方法
我们对一例伴t(3;11)(q29q13;p15)的原发性急性杂合性白血病进行了深入研究,充分利用当前人类基因组研究所取得的大量信息,采取了定位候选基因克隆策略(positional candidate gene approaches),定位克隆t(3;11)(q29q13;p15)染色体易位的受累基因,进而对NUP98相关融合蛋白的致白血病机制进行了初步的研究。
第一部分:首先通过常规的分子-细胞遗传学方法检测出t(3;11)( q13;p15)染色体易位,并将11号染色体上的断裂点初步定位于11p15的NUP98基因3’端;接着通过cDNA末端快速扩增技术(Rapid Amplification of cDNA Ends, RACE)发现了位于3q29的NUP98伙伴基因NRG(因当时GeneBank无此基因的详细信息,我们姑且命名为NUP98 Related Gene);为了解释RACE结果与核型检测不符之处,我们选取了位于3q21和位于3q29的两个BAC克隆来分析3号染色体复杂异常情
Objective
Leukemia is a kind of malignant tumor of hematopoietic system doing severely harm to human health, always with non-random cytogenetic abnormalities, among which the most frequency is chromosomal translocation. It can be seen in 65% acute leukemia patients. Mostly targed genes of chromosomal translocation are transcriptional factor or trosine-protein kinase, resulting in dysregulative pathwalys of cell proliferation, apoptosis, differentiation and playing an important role in leukemogenesis. Therefore, detection of the recurrent chromosomal translocations, molecular cloning and functional study of the involved genes will shed light on deciphering the molecular mechanisms of leukemogenesis, provide diagnostic markers and allow the development of new therapeutic strategies. In recent years, chromosome aberration involving 11p15 has been reported increasingly. To date at least 17 kinds have been identified. Almost all 11p15 translocations targed the NUP98 gene located at chromosome 11p15. Our work is to provide considerable insight into the mechanisms of NUP98-related fusion genes in leukemia through molecular cloning and functional study of the fusion genes by the chromosome translocation t(3;11)(q29q13;p15) in a hybrid acute leukemia patient Furthermore,it will help to diagnose, guide risk-directed therapy for leukemia.
Methods
We investigated an adult patient with the chromosome translocation t(3;11)(q29q13;p15) in de novo hybrid acute leukemia. With positional candidate gene approaches, we characterized the genes involved in that translocation and subsequently studied the function of the fusion protein in leukemogenic mechanism.
Part I: Firstly, through molecular genetic-cytogenetics, we identified a new chromosomal translocation t(3;11)( q13;p15) and located chromosome breakpoint at the NUP98 gene at 11p15. Using Rapid Amplification of cDNA Ends (RACE), we
引文
1. Look AT. Oncogenic transcription factors in the human acute leukemias. Science 1997; 278: 1059–1064.
2. Rowley JD. The critical role of chromosome translocations in human leukemias. Annu Rev Genet 1998; 32: 495–519.
3. Rabbitts TH. Chromosomal translocations in human cancer. Nature 1994; 372: 143–149
4. Cline MJ. The molecular basis of leukemia. N Engl J Med 1994;330: 328–336.
5. Nakamura T, Largaespada DA, Lee MP, et al. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet 1996;12(2): 154-158.
6. Borrow J, Shearman AM, Stanton VP, et al. The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nat Genet 1996;12(2): 159-167.
7. Raza-Egilmez SZ, Jani-Sait SN, Grossi M, et al. NUP98-HOXD13 gene fusion in therapy- related acute myelogenous leukemia. Cancer Res 1998;58: 4269-4273.
8. Nakamura T, Yamazaki Y, Hatano Y, et al. NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15). Blood 1999 ;94: 741-747.
9. Arai Y, Hosoda F, Kobayashi H, et al. The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. Blood 1997;89: 3936-3944.
10. Hussey DJ, Nicola M, Moore S, et al. The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia. Blood 1999;94(6): 2072-2079.
11. Ahuja HG, Felix CA, Aplan PD. The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion. Blood 1999;94: 3258-3261.
12. Ahuja HG, Hong J, Aplan PD, et al. t(9;11)(p22;p15) in acute myeloid leukemia results in a fusion between NUP98 and the gene encoding transcriptional coactivators p52 and p75-lens epithelium-derived growth factor (LEDGF). Cancer Res 2000;60:6227-6229.
13. Jaju RJ, Fidler C, Haas OA, et al. A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Blood 2001;98:1264-1267.
14. Hussey DJ, Moore S, Nicola M, et al. Fusion of the NUP98 gene with the LEDGF/p52 gene defines a recurrent acute myeloid leukemia translocation. BMC Genet 2001;2:20.
15. Taketani T, Taki T, Ono R, et al. The chromosome translocation t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with a HOXA cluster gene, HOXA13, but not HOXA9. Genes Chromosomes Cancer 2002a;34:437-443.
16. Taketani T, Taki T, Shibuya N, et al. The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15). Cancer Res 2002b;62:33-37.
17. Taketani T, Taki T, Shibuya N, et al. 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). Cancer Res 2002c;62:4571-4574.
18. Suzuki A, Ito Y, Sashida G, et al. t(7;11)(p15;p15) Chronic myeloid leukaemia developed into blastic transformation showing a novel NUP98/HOXA11 fusion. Br J Haematol 2002;116:170-172.
19. Rosati R, La Starza R, Veronese A, et al. NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Blood 2002;99:3857-3860.
20. Lahortiga I, Vizmanos JL, Agirre X, 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 2003;63(12):3079-3083.
21. Gu BW, Wang Q, Wang JM, et al. Major form of NUP98/HOXC11 fusion in adult AML with t(11;12)(p15;q13) translocation exhibits aberrant trans-regulatory activity. Leukemia 2003;17:1858-1864.
22. Panagopoulos I, Isaksson M, Billstrom R,et al. Fusion of the NUP98 gene and thehomeobox gene HOXC13 in acute myeloid leukemia with t(11;12)(p15;q13). Genes Chromosomes Cancer 2003;36:107-112.
23. Gervais C, Mauvieux L, Perrusson N, et al.A new translocation t(9;11)(q34;p15) fuses NUP98 to a novel homeobox partner gene, PRRX2, in a therapy-related acute myeloid leukemia .Leukemia. 2005;19:145-148.
24. Tosi S, Ballabio E, Teigler-Schlegel A, et al. Characterization of 6q abnormalities in childhood acute myeloid leukemia and identification of a novel t(6;11)(q24.1;p15.5) resulting in a NUP98-C6orf80 fusion in a case of acute megakaryoblastic leukemia. Genes Chromosomes Cancer, 2005;44:225-232.
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1. Rabbitts TH. Chromosomal translocations in human cancer. Nature 1994; 372: 143–149
2. Cline MJ. The molecular basis of leukemia. N Engl J Med 1994;330: 328–336.
3. Look AT. Oncogenic transcription factors in the human acute leukemias. Science 1997; 278: 1059–1064.
4. Nakamura T, Largaespada DA, Lee MP, et al. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet 1996;12(2): 154-158.
5. Borrow J, Shearman AM, Stanton VP, et al. The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nat Genet 1996;12(2): 159-167.
6. Raza-Egilmez SZ, Jani-Sait SN, Grossi M, et al. NUP98-HOXD13 gene fusion in therapy- related acute myelogenous leukemia. Cancer Res 1998;58: 4269-4273.
7. Nakamura T, Yamazaki Y, Hatano Y, et al. NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15). Blood 1999 ;94: 741-747.
8. Arai Y, Hosoda F, Kobayashi H, et al. The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. Blood 1997;89: 3936-3944.
9. Hussey DJ, Nicola M, Moore S, et al. The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia. Blood 1999;94(6): 2072-2079.
10. Ahuja HG, Felix CA, Aplan PD. The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion. Blood 1999;94: 3258-3261.
11. Ahuja HG, Hong J, Aplan PD, et al. t(9;11)(p22;p15) in acute myeloid leukemia results in a fusion between NUP98 and the gene encoding transcriptional coactivators p52 and p75-lens epithelium-derived growth factor (LEDGF). Cancer Res 2000;60:6227-6229.
12. Jaju RJ, Fidler C, Haas OA, et al. A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Blood2001;98:1264-1267.
13. Hussey DJ, Moore S, Nicola M, et al. Fusion of the NUP98 gene with the LEDGF/p52 gene defines a recurrent acute myeloid leukemia translocation. BMC Genet 2001;2:20.
14. Taketani T, Taki T, Ono R, et al. The chromosome translocation t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with a HOXA cluster gene, HOXA13, but not HOXA9. Genes Chromosomes Cancer 2002a;34:437-443.
15. Taketani T, Taki T, Shibuya N, et al. The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15). Cancer Res 2002b;62:33-37.
16. Taketani T, Taki T, Shibuya N, et al. 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). Cancer Res 2002c;62:4571-4574.
17. Suzuki A, Ito Y, Sashida G, et al. t(7;11)(p15;p15) Chronic myeloid leukaemia developed into blastic transformation showing a novel NUP98/HOXA11 fusion. Br J Haematol 2002;116:170-172.
18. Rosati R, La Starza R, Veronese A, et al. NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Blood 2002;99:3857-3860.
19. Lahortiga I, Vizmanos JL, Agirre X, 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 2003;63(12):3079-3083.
20. Gu BW, Wang Q, Wang JM, et al. Major form of NUP98/HOXC11 fusion in adult AML with t(11;12)(p15;q13) translocation exhibits aberrant trans-regulatory activity. Leukemia 2003;17:1858-1864.
21. Panagopoulos I, Isaksson M, Billstrom R,et al. Fusion of the NUP98 gene and the homeobox gene HOXC13 in acute myeloid leukemia with t(11;12)(p15;q13). Genes Chromosomes Cancer 2003;36:107-112.
22. Tosi S, Ballabio E, Teigler-Schlegel A, et al. Characterization of 6q abnormalities in childhood acute myeloid leukemia and identification of a novel t(6;11)(q24.1;p15.5) resulting in a NUP98-C6orf80 fusion in a case of acute megakaryoblastic leukemia.Genes Chromosomes Cancer, 2005;44:225-232.
23. Gervais C, Mauvieux L, Perrusson N, et al.A new translocation t(9;11)(q34;p15) fuses NUP98 to a novel homeobox partner gene, PRRX2, in a therapy-related acute myeloid leukemia .Leukemia. 2005;19:145-148.
24. Griffis ER, Xu S, Powers MA. Nup98 localizes to both nuclear and cytoplasmic sides of the nuclear pore and binds to two distinct nucleoporin subcomplexes.Mol Biol Cell 2003;14(2):600 - 610.
25. Fujino T, Suzuki A, Ito Y, et al. Single-translocation and double-chimeric transcripts: detection of NUP98-HOXA9 in myeloid leukemias with HOXA11 or HOXA13 breaks of the chromosomal translocation t(7;11)(p15;p15). Blood 2002; 99(4):1428-33
26. Suzuki A, Ito Y, Sashida G, et al.t(7;11)(p15;p15) Chronic myeloid leukaemia developed into blastic transformation showing a novel NUP98/HOXA11 fusion. Br J Haematol 2002;116(1):170-2
27. Taketani T, Taki T, Ono R, et al. The chromosome translocation t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with a HOXA cluster gene, HOXA13, but not HOXA9. Genes Chromosomes Cancer 2002;34(4):437-43
28. Nishiyama M, Arai Y, Tsunematsu Y, et al. 11p15 translocations involving the NUP98 gene in childhood therapy-related acute myeloid leukemia/myelodysplastic syndrome. Genes Chromosomes Cancer 1999;26(3):215-20.
29. Fontoura BM, Blobel G, Matunis MJ. A conserved biogenesis pathway for nucleoporins: proteolytic processing of a 186-kilodalton precursor generates Nup98 and the novel nucleoporin,Nup96. Journal of Cell Biology 1999;144(6):1097 – 1112.
30. Powers MA, Forbes DJ, Dahlberg JE,et al. The vertebrate GLFG nucleoporin, Nup98, is an essential component of multiple RNA export pathways’’, Journal of Cell Biology 1997; 136(2): 241 – 250.
31. Fontoura BM, Blobel G, Yaseen NR. The nucleoporin Nup98 is a site for GDP/GTP exchange on ran and termination of karyopherin beta 2-mediated nuclear import. JBiol Chem 2000; 275(40): 31289–31296.
32. Pritchard CE, Fornerod M, Kasper LH, et al. RAE1 is a shuttling mRNA export factor that binds to a GLEBS-like NUP98 motif at the nuclear pore complex through multiple domains. J Cell Biol 1999;145(2), 237-254.
33. Strasser K., Bassler J , Hurt E. Binding of the Me×67p/Mtr2p heterodimer to FxFG, GLFG, and FG repeat nucleoporins is essential for nuclear mRNA export. J Cell Biol 2000;150(4): 695-706.
34. Bachi A., Braun IC, Rodrigues JP, et al. The C-terminal domain of TAP interacts with the nuclear pore complex and promotes export of speci.c CTE-bearing RNA substrates. RNA 2000;6(1):136-158.
35. Kasper LH, Brindle PK, Schnabel CA, et al. CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. Mol Cell Biol 1999;19(1):764-776.
36. Gehring WJ, Aolter M, Burglin, T. Homeodomain proteins. Annu Rev Biochem 1994; 63: 487 – 526.
37. Shen WF, Rozenfeld S, Kwong A, et al. HOXA9 forms triple complexes with PBX2 and MEIS1 in myeloid cells. Mol Cell Biol 1999; 19(4): 3051–3061.
38. Kroon E, Krosl J, Thorsteinsdottir U, et al. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pb61b. EMBO J 1998;17(13):3714 – 3725.
39. Shen WF, Montgomery JC, Rozenfeld S, et al. AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins. Mol Cell Biol 1997;17(11): 6448 – 6458.
40. Hussey DJ, Dobrovic A. Recurrent coiled-coil motifs in NUP98 fusion partners provide a clue to leukemogenesis. Blood 2002; 99(3):1097-8.
41. Wu X, Kasper LH, Mantcheva RT, et al. Disruption of the FG nucleoporin NUP98 causes selective changes in nuclear pore complex stoichiometry and function.Proc Natl Acad Sci U S A. 2001;98(6):3191-3196.
42. Calvo KR, Sykes DB, Pasillas MP,et al. Nup98-HoxA9 immortalizes myeloidprogenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1.Oncogene. 2002 Jun 20;21(27):4247-56.
43. Kroon E, Thorsteinsdottir U, Mayotte N, et al.NUP98-HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice. EMBO J 2001; 20(3):350-61.
44. Iwasaki M, Kuwata T, Yamazaki Y, et al. Identification of cooperative genes for NUP98-HOXA9 in myeloid leukemogenesis using a mouse model. Blood 2005;105(2):784-93.
45. Dash AB,Williams IR, Kutok JL, et al. A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc Nat Acad Sci U S A 2002; 99(11):7622-7627
46. Lu SY, Gu MM, Wang Y,et al. HUP98-HOXA9 transgenic mice are susceptible to N-ethyl-N-nitrosourea stimulation in leukemogenesis.Zhonghua Xue Ye Xue Za Zhi 2004;25(5):257-261
47. Lin YW,Slape C, Zhang Z, et al. NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia. Blood. 2005;
48. Minucci S, Maccarana M, Cioce M, et al. Oligomerization of RARα and AML1 transcription factors as a novel mechanism of oncogenic activation. Mol Cell. 2000;5:811-820.
49. Gurevich RM, Pineault N, Aplan PD,et al. The NUP98-Topoisomerase I (NUP98-TOP1) Fusion Associated with t(11;20) Can Induce Marked Myeloproliferation Independent of a Mutation Designed to Block TOP1 Catalytic Activity. Blood 2002;100(11):135a.
2. Rowley JD. The critical role of chromosome translocations in human leukemias. Annu Rev Genet 1998; 32: 495–519.
3. Rabbitts TH. Chromosomal translocations in human cancer. Nature 1994; 372: 143–149
4. Cline MJ. The molecular basis of leukemia. N Engl J Med 1994;330: 328–336.
5. Nakamura T, Largaespada DA, Lee MP, et al. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet 1996;12(2): 154-158.
6. Borrow J, Shearman AM, Stanton VP, et al. The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nat Genet 1996;12(2): 159-167.
7. Raza-Egilmez SZ, Jani-Sait SN, Grossi M, et al. NUP98-HOXD13 gene fusion in therapy- related acute myelogenous leukemia. Cancer Res 1998;58: 4269-4273.
8. Nakamura T, Yamazaki Y, Hatano Y, et al. NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15). Blood 1999 ;94: 741-747.
9. Arai Y, Hosoda F, Kobayashi H, et al. The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. Blood 1997;89: 3936-3944.
10. Hussey DJ, Nicola M, Moore S, et al. The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia. Blood 1999;94(6): 2072-2079.
11. Ahuja HG, Felix CA, Aplan PD. The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion. Blood 1999;94: 3258-3261.
12. Ahuja HG, Hong J, Aplan PD, et al. t(9;11)(p22;p15) in acute myeloid leukemia results in a fusion between NUP98 and the gene encoding transcriptional coactivators p52 and p75-lens epithelium-derived growth factor (LEDGF). Cancer Res 2000;60:6227-6229.
13. Jaju RJ, Fidler C, Haas OA, et al. A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Blood 2001;98:1264-1267.
14. Hussey DJ, Moore S, Nicola M, et al. Fusion of the NUP98 gene with the LEDGF/p52 gene defines a recurrent acute myeloid leukemia translocation. BMC Genet 2001;2:20.
15. Taketani T, Taki T, Ono R, et al. The chromosome translocation t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with a HOXA cluster gene, HOXA13, but not HOXA9. Genes Chromosomes Cancer 2002a;34:437-443.
16. Taketani T, Taki T, Shibuya N, et al. The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15). Cancer Res 2002b;62:33-37.
17. Taketani T, Taki T, Shibuya N, et al. 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). Cancer Res 2002c;62:4571-4574.
18. Suzuki A, Ito Y, Sashida G, et al. t(7;11)(p15;p15) Chronic myeloid leukaemia developed into blastic transformation showing a novel NUP98/HOXA11 fusion. Br J Haematol 2002;116:170-172.
19. Rosati R, La Starza R, Veronese A, et al. NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Blood 2002;99:3857-3860.
20. Lahortiga I, Vizmanos JL, Agirre X, 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 2003;63(12):3079-3083.
21. Gu BW, Wang Q, Wang JM, et al. Major form of NUP98/HOXC11 fusion in adult AML with t(11;12)(p15;q13) translocation exhibits aberrant trans-regulatory activity. Leukemia 2003;17:1858-1864.
22. Panagopoulos I, Isaksson M, Billstrom R,et al. Fusion of the NUP98 gene and thehomeobox gene HOXC13 in acute myeloid leukemia with t(11;12)(p15;q13). Genes Chromosomes Cancer 2003;36:107-112.
23. Gervais C, Mauvieux L, Perrusson N, et al.A new translocation t(9;11)(q34;p15) fuses NUP98 to a novel homeobox partner gene, PRRX2, in a therapy-related acute myeloid leukemia .Leukemia. 2005;19:145-148.
24. Tosi S, Ballabio E, Teigler-Schlegel A, et al. Characterization of 6q abnormalities in childhood acute myeloid leukemia and identification of a novel t(6;11)(q24.1;p15.5) resulting in a NUP98-C6orf80 fusion in a case of acute megakaryoblastic leukemia. Genes Chromosomes Cancer, 2005;44:225-232.
25. Nishiyama M, Arai Y, Tsunematsu Y, et al. 11p15 translocations involving the NUP98 gene in childhood therapy-related acute myeloid leukemia/myelodysplastic syndrome. Genes Chromosomes Cancer 1999; 26: 215-220.
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30. Moroianu J, Blobel G, Radu A. RanGTP-mediated nuclear export of karyopherin alpha involves its interaction with the nucleoporin Nup153. Proc Natl Acad Sci 1997; 94: 9699–9704.
31. Fontoura BM., Blobel G and Matunis MJ. A conserved biogenesis pathway for nucleoporins: proteolytic processing of a 186-kilodalton precursor generates Nup98 and the novel nucleoporin,Nup96. Journal of Cell Biology 1999;144(6):1097-1112.
32. Powers MA, Forbes DJ, Dahlberg JE,et al. The vertebrate GLFG nucleoporin, Nup98, is an essential component of multiple RNA export pathways. Journal of Cell Biology, 1997;136(2): 241-250.
33. Pritchard CE, Fornerod M, Kasper LH, et al. RAE1 is a shuttling mRNA export factor that binds to a GLEBS-like NUP98 motif at the nuclear pore complex through multiple domains. J Cell Biol 1999;145(2), 237-254.
34. Strasser K, Bassler J, Hurt E. Binding of the Me×67p/Mtr2p heterodimer to FxFG, GLFG, and FG repeat nucleoporins is essential for nuclear mRNA export. J Cell Biol 2000;150(4): 695-706.
35. Bachi A, Braun IC, Rodrigues JP, et al. The C-terminal domain of TAP interacts with the nuclear pore complex and promotes export of speci.c CTE-bearing RNA substrates. RNA 2000;6(1):136-158.
36. Griffis ER, Altan N, Lippincott-Schwartz, et al. Nup98 is a mobile nucleoporin with transcription-dependent dynamics. Mol Biol Cell 2002;13(4): 1282-1297.
37. Kasper LH, Brindle PK, Schnabel CA, et al. CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. Mol Cell Biol 1999;19(1):764-776.
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56. Fontoura BM, Blobel G, Yaseen NR. The nucleoporin Nup98 is a site for GDP/GTP exchange on ran and termination of karyopherin beta 2-mediated nuclear import. J Biol Chem 2000; 275(40): 31289–31296.
57. Iwasaki M, Kuwata T, Yamazaki Y, et al. Identification of cooperative genes for NUP98-HOXA9 in myeloid leukemogenesis using a mouse model. Blood 2005;105(2):784-93.
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1. Rabbitts TH. Chromosomal translocations in human cancer. Nature 1994; 372: 143–149
2. Cline MJ. The molecular basis of leukemia. N Engl J Med 1994;330: 328–336.
3. Look AT. Oncogenic transcription factors in the human acute leukemias. Science 1997; 278: 1059–1064.
4. Nakamura T, Largaespada DA, Lee MP, et al. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet 1996;12(2): 154-158.
5. Borrow J, Shearman AM, Stanton VP, et al. The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nat Genet 1996;12(2): 159-167.
6. Raza-Egilmez SZ, Jani-Sait SN, Grossi M, et al. NUP98-HOXD13 gene fusion in therapy- related acute myelogenous leukemia. Cancer Res 1998;58: 4269-4273.
7. Nakamura T, Yamazaki Y, Hatano Y, et al. NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15). Blood 1999 ;94: 741-747.
8. Arai Y, Hosoda F, Kobayashi H, et al. The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. Blood 1997;89: 3936-3944.
9. Hussey DJ, Nicola M, Moore S, et al. The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia. Blood 1999;94(6): 2072-2079.
10. Ahuja HG, Felix CA, Aplan PD. The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion. Blood 1999;94: 3258-3261.
11. Ahuja HG, Hong J, Aplan PD, et al. t(9;11)(p22;p15) in acute myeloid leukemia results in a fusion between NUP98 and the gene encoding transcriptional coactivators p52 and p75-lens epithelium-derived growth factor (LEDGF). Cancer Res 2000;60:6227-6229.
12. Jaju RJ, Fidler C, Haas OA, et al. A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Blood2001;98:1264-1267.
13. Hussey DJ, Moore S, Nicola M, et al. Fusion of the NUP98 gene with the LEDGF/p52 gene defines a recurrent acute myeloid leukemia translocation. BMC Genet 2001;2:20.
14. Taketani T, Taki T, Ono R, et al. The chromosome translocation t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with a HOXA cluster gene, HOXA13, but not HOXA9. Genes Chromosomes Cancer 2002a;34:437-443.
15. Taketani T, Taki T, Shibuya N, et al. The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15). Cancer Res 2002b;62:33-37.
16. Taketani T, Taki T, Shibuya N, et al. 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). Cancer Res 2002c;62:4571-4574.
17. Suzuki A, Ito Y, Sashida G, et al. t(7;11)(p15;p15) Chronic myeloid leukaemia developed into blastic transformation showing a novel NUP98/HOXA11 fusion. Br J Haematol 2002;116:170-172.
18. Rosati R, La Starza R, Veronese A, et al. NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Blood 2002;99:3857-3860.
19. Lahortiga I, Vizmanos JL, Agirre X, 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 2003;63(12):3079-3083.
20. Gu BW, Wang Q, Wang JM, et al. Major form of NUP98/HOXC11 fusion in adult AML with t(11;12)(p15;q13) translocation exhibits aberrant trans-regulatory activity. Leukemia 2003;17:1858-1864.
21. Panagopoulos I, Isaksson M, Billstrom R,et al. Fusion of the NUP98 gene and the homeobox gene HOXC13 in acute myeloid leukemia with t(11;12)(p15;q13). Genes Chromosomes Cancer 2003;36:107-112.
22. Tosi S, Ballabio E, Teigler-Schlegel A, et al. Characterization of 6q abnormalities in childhood acute myeloid leukemia and identification of a novel t(6;11)(q24.1;p15.5) resulting in a NUP98-C6orf80 fusion in a case of acute megakaryoblastic leukemia.Genes Chromosomes Cancer, 2005;44:225-232.
23. Gervais C, Mauvieux L, Perrusson N, et al.A new translocation t(9;11)(q34;p15) fuses NUP98 to a novel homeobox partner gene, PRRX2, in a therapy-related acute myeloid leukemia .Leukemia. 2005;19:145-148.
24. Griffis ER, Xu S, Powers MA. Nup98 localizes to both nuclear and cytoplasmic sides of the nuclear pore and binds to two distinct nucleoporin subcomplexes.Mol Biol Cell 2003;14(2):600 - 610.
25. Fujino T, Suzuki A, Ito Y, et al. Single-translocation and double-chimeric transcripts: detection of NUP98-HOXA9 in myeloid leukemias with HOXA11 or HOXA13 breaks of the chromosomal translocation t(7;11)(p15;p15). Blood 2002; 99(4):1428-33
26. Suzuki A, Ito Y, Sashida G, et al.t(7;11)(p15;p15) Chronic myeloid leukaemia developed into blastic transformation showing a novel NUP98/HOXA11 fusion. Br J Haematol 2002;116(1):170-2
27. Taketani T, Taki T, Ono R, et al. The chromosome translocation t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with a HOXA cluster gene, HOXA13, but not HOXA9. Genes Chromosomes Cancer 2002;34(4):437-43
28. Nishiyama M, Arai Y, Tsunematsu Y, et al. 11p15 translocations involving the NUP98 gene in childhood therapy-related acute myeloid leukemia/myelodysplastic syndrome. Genes Chromosomes Cancer 1999;26(3):215-20.
29. Fontoura BM, Blobel G, Matunis MJ. A conserved biogenesis pathway for nucleoporins: proteolytic processing of a 186-kilodalton precursor generates Nup98 and the novel nucleoporin,Nup96. Journal of Cell Biology 1999;144(6):1097 – 1112.
30. Powers MA, Forbes DJ, Dahlberg JE,et al. The vertebrate GLFG nucleoporin, Nup98, is an essential component of multiple RNA export pathways’’, Journal of Cell Biology 1997; 136(2): 241 – 250.
31. Fontoura BM, Blobel G, Yaseen NR. The nucleoporin Nup98 is a site for GDP/GTP exchange on ran and termination of karyopherin beta 2-mediated nuclear import. JBiol Chem 2000; 275(40): 31289–31296.
32. Pritchard CE, Fornerod M, Kasper LH, et al. RAE1 is a shuttling mRNA export factor that binds to a GLEBS-like NUP98 motif at the nuclear pore complex through multiple domains. J Cell Biol 1999;145(2), 237-254.
33. Strasser K., Bassler J , Hurt E. Binding of the Me×67p/Mtr2p heterodimer to FxFG, GLFG, and FG repeat nucleoporins is essential for nuclear mRNA export. J Cell Biol 2000;150(4): 695-706.
34. Bachi A., Braun IC, Rodrigues JP, et al. The C-terminal domain of TAP interacts with the nuclear pore complex and promotes export of speci.c CTE-bearing RNA substrates. RNA 2000;6(1):136-158.
35. Kasper LH, Brindle PK, Schnabel CA, et al. CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. Mol Cell Biol 1999;19(1):764-776.
36. Gehring WJ, Aolter M, Burglin, T. Homeodomain proteins. Annu Rev Biochem 1994; 63: 487 – 526.
37. Shen WF, Rozenfeld S, Kwong A, et al. HOXA9 forms triple complexes with PBX2 and MEIS1 in myeloid cells. Mol Cell Biol 1999; 19(4): 3051–3061.
38. Kroon E, Krosl J, Thorsteinsdottir U, et al. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pb61b. EMBO J 1998;17(13):3714 – 3725.
39. Shen WF, Montgomery JC, Rozenfeld S, et al. AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins. Mol Cell Biol 1997;17(11): 6448 – 6458.
40. Hussey DJ, Dobrovic A. Recurrent coiled-coil motifs in NUP98 fusion partners provide a clue to leukemogenesis. Blood 2002; 99(3):1097-8.
41. Wu X, Kasper LH, Mantcheva RT, et al. Disruption of the FG nucleoporin NUP98 causes selective changes in nuclear pore complex stoichiometry and function.Proc Natl Acad Sci U S A. 2001;98(6):3191-3196.
42. Calvo KR, Sykes DB, Pasillas MP,et al. Nup98-HoxA9 immortalizes myeloidprogenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1.Oncogene. 2002 Jun 20;21(27):4247-56.
43. Kroon E, Thorsteinsdottir U, Mayotte N, et al.NUP98-HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice. EMBO J 2001; 20(3):350-61.
44. Iwasaki M, Kuwata T, Yamazaki Y, et al. Identification of cooperative genes for NUP98-HOXA9 in myeloid leukemogenesis using a mouse model. Blood 2005;105(2):784-93.
45. Dash AB,Williams IR, Kutok JL, et al. A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc Nat Acad Sci U S A 2002; 99(11):7622-7627
46. Lu SY, Gu MM, Wang Y,et al. HUP98-HOXA9 transgenic mice are susceptible to N-ethyl-N-nitrosourea stimulation in leukemogenesis.Zhonghua Xue Ye Xue Za Zhi 2004;25(5):257-261
47. Lin YW,Slape C, Zhang Z, et al. NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia. Blood. 2005;
48. Minucci S, Maccarana M, Cioce M, et al. Oligomerization of RARα and AML1 transcription factors as a novel mechanism of oncogenic activation. Mol Cell. 2000;5:811-820.
49. Gurevich RM, Pineault N, Aplan PD,et al. The NUP98-Topoisomerase I (NUP98-TOP1) Fusion Associated with t(11;20) Can Induce Marked Myeloproliferation Independent of a Mutation Designed to Block TOP1 Catalytic Activity. Blood 2002;100(11):135a.