NUP98 Fusion in Human Leukemia: Dysregulation of the Nuclear Pore and Homeodomain Proteins

Abstract

NUP98 is fused to a variety of partner genes, including abdominal B-likeHOX, in human myeloid and T-cell malignancies via chromosomal translocation involving 11p15.NUP98 encodes a 98-kd nucleoporin that is a component of the nuclear pore complex and functions in nucleocytoplasmic transport, with its N-terminal GLFG repeats used as a docking site for karyopherins. Disruption of NUP98 may affect the nuclear pore function, and the abnormal expression and altered function of fusion partners may also be critical for leukemia development. Recent studies using mouse models expressingNUP98-HOX have confirmed its leukemogenic potential, and cooperative genes forNUP98-HOXA9 in leukemogenesis have been identified in these studies. Thus, the NUP98 chimera is a unique molecule that provides valuable information regarding nuclear pore function and the role of the homeobox protein in leukemogenesis/carcinogenesis.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Radu A, Moore MS, Brobel G. The peptide repeat domain of nucleoporin Nup98 functions as a docking site in transport across the nuclear pore complex.Cell. 1995;81:677–690.

    Article  Google Scholar 

  2. 2.

    Powers MA, Macaulay C, Masiarz FR, Forbes DJ. Reconstituted nuclei depleted of a vertebrate GLFG nuclear pore protein, p97, import but are defective in nuclear growth and replication.J. Biol Chem. 1995;128:721–736.

    CAS  Google Scholar 

  3. 3.

    Nakamura T, Largaespada DA, Lee MP, et al. Fusion of the nucleoporin geneNUP98 toHOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia.Nat Genet. 1996;12:154–1588.

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    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;12:159–167.

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    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;89:3936–39444.

    PubMed  CAS  Google Scholar 

  6. 6.

    Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, Shows TB, Apian PD. NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia.Cancer Res. 1998;58:4269–4273.

    PubMed  CAS  Google Scholar 

  7. 7.

    Nakamura T, Yamazaki Y, Hatano Y, Miura I.NUP98 is fused toPMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15).Blood. 1999;94:741–7477.

    PubMed  CAS  Google Scholar 

  8. 8.

    Hussey DJ, Nicola M, Moore S, Peters GB, Dobrovic A. The (4;11) (q21;p15) translocation fuses theNUP98 andRAP1GDS genes and is recurrent in T-cell acute lymphocytic leukemia.Blood. 1999;94:2072–2079.

    PubMed  CAS  Google Scholar 

  9. 9.

    Ahuja HG, Felic CA, Apian PD. The t(11;20)(p15;q15) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in anNUP98-TOP1 fusion.Blood. 1999;94:3258–32611.

    PubMed  CAS  Google Scholar 

  10. 10.

    Jaju RJ, Fidler C, Haas OA, et al. A novel gene,NSD1, is fused toNUP98 in the t(5;11)(q35;p15) in de novo childhood acute myeloid leukemia.Blood. 2001;98:1264–1267.

    Article  CAS  Google Scholar 

  11. 11.

    Taketani T, Taki T, Shibuya N, et al. TheHOXD11 gene is fused to theNUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15).Cancer Res. 2002;62:33–37.

    PubMed  PubMed Central  CAS  Google Scholar 

  12. 11.

    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. 2002;62:4571–4574.

    PubMed  CAS  Google Scholar 

  13. 13.

    Ahuja HG, Hong J, Apian PD, et al. t(9;11)(p22;p15) in acute myeloid leukemia results in a fusion betweenNUP98 and the gene encoding transcriptional coactivators p52 and p75-lens epithelium- derived growth factor (LEDGF).Cancer Res. 2000;60:6227–6229.

    PubMed  CAS  Google Scholar 

  14. 14.

    Fujino T, Suzuki A, Ito Y, et al. Single-translocation and double- chimeric transcripts: detection ofNUP98-HOXA9 in myeloid leukemias withHOXA11 orHOXA13 breaks of the chromosomal translocation t(7;11)(p15;p15).Blood. 2002;99:1428–1433.

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Rosati R, La Starza R, Veronese A, et al.NUP98 is fused to theNSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15).Blood. 2002;99:3857–3860.

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Panagopoulos I, Isaksson M, Billstrom R, Strombeck B, Mitelman F, Johansson B. Fusion of theNUP98 gene and the homeobox geneHOXC13 in acute myeloid leukemia with t(11;12)(p15;q13).Genes Chromosomes Cancer. 2003;36:107–112.

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Lahortiga I, Vizmanos JL, Agirre X, et al.NUP98 is fused toAdducin 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;63:3079–3083.

    PubMed  CAS  Google Scholar 

  18. 18.

    Nakielny S, Dreyfuss G. Transport of proteins and RNAs in and out of the nucleus.Cell. 1999;99:677–690.

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    Rout MP, Wente SR. Pores for thought: nuclear pore complex proteins.Trends Genet. 1994;4:357–365.

    CAS  Google Scholar 

  20. 20.

    Rout MP, Aitchison JD, Suprapto A, Hjertaas K, Zhao Y, Chai BT. The yeast nuclear pore complex: composition, architecture, and transport mechanism.J. Cell Biol. 2000;148:635–651.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. 21.

    Cronshaw JM, Krutchinsky AN, Zhang W, Chait BT, Matunis MJ. Proteomic analysis of the mammalian nuclear pore complex.J. Cell Biol. 2002;158:915–927.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. 22.

    Rosenblum JS, Blobel G. Autoproteolysis in nucleoporin biogenesis.Proc Natl Acad Sci USA. 1999;96:11370–11375.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. 23.

    Fontoura BM, Blobel G, Matunis MX. A conserved biogenesis pathway for nucleoporins: proteolytic processing of a 186-kilodalton precursor generates Nup98 and the novel nucleoporin Nup96.J. Cell Biol. 1999;144:1097–1112.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. 24.

    Griffls 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;14:600–610.

    Article  Google Scholar 

  25. 25.

    Fornerod M, van DeursenJ, van Baal S, et al. The human homologue of yeast CRM1 is in a dynamic subcomplex with CAN/ Nup214 and a novel nuclear pore component Nup88.EMBO J. 1997;16:807–816.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. 26.

    Neville M, Stutz F, Lee L, Davis LI, Rosbash M. The importin-beta family member Crmlp bridges the interaction between Rev and the nuclear pore complex during nuclear export.Curr Biol. 1997;7:767–7755.

    Article  PubMed  CAS  Google Scholar 

  27. 27.

    Pritchard CE, Fornerod M, Kasper KH, van Deursen JM. 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;145:237–254.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. 28.

    Blevins MB, Smith AM, Phillips EM, Powers MA. Complex formation among the RNA export proteins Nup98, Rael/Gle2 and TAP.J. Biol Chem. 2003;278:20979–20988.

    Article  PubMed  CAS  Google Scholar 

  29. 29.

    Dasso M. Running on Ran: nuclear transport and the mitotic spindle.Cell. 2001;104:321–324.

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Stoffler D, Goldie KN, Feja B, Aebi U. Calcium-mediated structural changes of nuclear pore complexes monitored by time-lapse atomic force microscopy.J. Mol Biol. 1999;287:741–752.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. 31.

    Griffls ER, Altan N, Lippincott-Schwartz J, Powers MA. Nup98 is a mobile nucleoporin with transcription-dependent dynamics.Mol Biol Cell. 2002;13:1282–1297.

    Article  CAS  Google Scholar 

  32. 32.

    Zolotukhin AS, Felber BK. Nucleoporins Nup98 and Nup214 participate in nuclear export of human immunodeficiency virus type 1 Rev.J. Virol. 1999;73:120–127.

    PubMed  PubMed Central  CAS  Google Scholar 

  33. 33.

    Wu X, Kasper LH, Mantcheva RT, Matchev GT, Springett MJ, van DeursenJM. Disruption of the FG nucleoporin NUP98 causes selective changes in nuclear pore complex stoichiometry and function.Proc Natl Acad Sci USA. 2001;98:3191–3196.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. 34.

    von LindernM, Fornerod M, van Baal S, et al. The translocation (6;9), associated with a specific subtype of acute myeloid leukemia, results in the fusion of two genes, dek and can, and the expression of a chimeric, leukemia-specific dek-can mRNA.Mol Cell Biol. 1992;12:1687–1697.

    Article  Google Scholar 

  35. 35.

    Kau TR, Way JC, Silver PA. Nuclear transport and cancer: from mechanism to intervention.Nat Rev Cancer. 2004;4:106–117.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. 36.

    Kasper LH, Brindle PK, Schnabel CA, Pritchard CE, Cleary ML, van DeursenJM. CREB binding protein interacts with nucleo- porin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity.Mol Cell Biol. 1999;19:764–776.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. 37.

    Ghannam G,Takeda A, CamarataT, Moore MA, Viale A, Yaseen NR. The oncogeneNup98-HOXA9 induces gene transcription in myeloid cells.J. Biol Chem. 2004;279:866–875.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. 38.

    Hussey DJ, Dobrovic A. Recurrent coiled-coil motifs in NUP98 fusion partners provide a clue to leukemogenesis.Blood. 2002;99:1097–10988.

    Article  CAS  Google Scholar 

  39. 39.

    Fontoura BMA, Dales S, Blobel G, Zhong H. The nucleoporin Nup98 associates with the intranuclear filamentous protein network of TPR.Proc Natl Acad Sci USA. 2001;98:3208–3213.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. 40.

    Krull S, Thyberg J, Bjorkroth B, Rackwitz HR, Cordes VC. Nucleoporins as components of the nuclear pore complex core structure and Tpr as the architectural element of the nuclear basket.Mol Biol Cell. 2004;15:4261–4277.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. 41.

    Frosst P, Guan T, Subauste C, Hahn K, Gerace L. Tpr is localized within the nuclear basket of the pore complex and has a role in nuclear protein export.J. Cell Biol. 2002;156:617–630.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. 42.

    Askjaer P, Bachi A, Wilm M, et al. RanGTP-regulated interactions of CRM1 with nucleoporins and a shuttling DEAD-box helicase.Mol Cell Biol. 2002;156:617–630.

    Google Scholar 

  43. 43.

    Manak JR, Scott MP. A class act: conservation of homeodomain protein functions.Development. 1994;120(suppl):61–71.

    Google Scholar 

  44. 44.

    Kehrl JH. Homeobox genes in hematopoiesis.Crit Rev Oncol Hematol. 1994;16:145–156.

    Article  PubMed  CAS  Google Scholar 

  45. 45.

    Lawrence HJ, Sauvageau G, Humphries RK, Largman C. The role of HOX homeobox genes in normal and leukemic hematopoiesis.Stem Cells. 1996;14:281–291.

    Article  PubMed  CAS  Google Scholar 

  46. 46.

    Sauvageau G, Lansdorp PM, Eaves CJ, et al. Differential expression of homeobox genes in functionally distinct CD34+ subpopulations of human bone marrow cells.Proc Natl Acad Sci USA. 1994; 91:12223–12227.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. 47.

    Thorsteinsdottir U, Sauvageau G, Hogh MR, et al. Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia.Mol Cell Biol. 1997;17:495–505.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. 48.

    Buske C, Feuring-Buske M, Antonchuk J, et al. Overexpression ofHOXA10 perturbs human lymphomyelopoiesis in vitro and in vivo.Blood. 2001;97:2286–2292.

    Article  PubMed  CAS  Google Scholar 

  49. 49.

    Care A, Valtieri M, Mattia G, et al. Enforced expression of HOXB7 promotes hematopoietic stem cell proliferation and myeloid- restricted progenitor differentiation.Oncogene. 1999;18:1993–2001.

    Article  PubMed  CAS  Google Scholar 

  50. 50.

    Fujino T, Yamazaki Y, Largaespada DA, et al. Inhibition of myeloid differentiation by Hoxa9, Hoxb8, and Meis homeobox genes.Exp Hematol. 2001;29:856–863.

    Article  PubMed  CAS  Google Scholar 

  51. 51.

    Krishnaraju K, Hoffman B, Liebermann DA. Lineage-specific regulation of hematopoiesis by HOX-B8 (HOX-2.4): inhibition of granulocytic differentiation and potentiation of monocytic differentiation.Blood. 1997;90:1840–1849.

    PubMed  CAS  Google Scholar 

  52. 52.

    Antonchuk J, Sauvageau R, Humphries RK. HOXB4-induced expansion of adult hematopoietic stem cells ex vivo.Cell. 2002;109:39–45.

    Article  PubMed  CAS  Google Scholar 

  53. 53.

    Kyba M, Perlingeiro RCR, Daley GQ. HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors.Cell. 2002;109:29–37.

    Article  PubMed  CAS  Google Scholar 

  54. 54.

    Stein S, Fritsch R, Lemnaire L, Kessel M. Checklist: vertebrate homeobox genes.Mech Dev. 1996;55:91–108.

    Article  PubMed  CAS  Google Scholar 

  55. 55.

    Lawrence HJ, Helgason CD, Sauvageau G, et al. Mice bearing a targeted interruption of the homeobox geneHOXA9 have defects in myeloid, erythroid, and lymphoid hematopoiesis.Blood. 1997;89:1922–19300.

    PubMed  CAS  Google Scholar 

  56. 56.

    Thompson AA, Nguyen LT. A megakaryocytic thrombocytopenia and radio-ulnar synostosis are associated withHOXA11 mutation.Nat Genet. 2000;26:397–399.

    Article  PubMed  CAS  Google Scholar 

  57. 57.

    Greaves MF, Wiemels J. Origins of chromosome translocation in childhood leukaemia.Nat Rev Cancer. 2003;3:1–11.

    Article  CAS  Google Scholar 

  58. 58.

    Kroon E, Thorsteinsdottir U, Mayotte N, Nakamura T, Sauvageau G. NUP98-HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice.EMBO J. 2001;20:350–3611.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. 59.

    Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg AM, Sauvageau G.Hoxa9 transforms primary bone marrow cells through specific collaboration withMeis1a but notPbx1b.EMBO J. 1998;17:3714–37255.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. 60.

    Pineault N, Buske C, Feuring-Buske M, et al. Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion geneNUP98-HOXD13 in concert withMeisl.Blood. 2003;101:4529–4538.

    Article  PubMed  CAS  Google Scholar 

  61. 61.

    Pineault N, Abramovich C, Ohta H, Humphries RK. Differential and common leukemogenic potentials of multiple NUP98-Hox fusion proteins alone or with Meisl.Mol Cell Biol. 2004;24:1907–1917.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. 62.

    Gurevich RM, Aplan PD, Humphries RK.NUP98-Topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation.Blood. 2004;104:1127–1136.

    Article  PubMed  CAS  Google Scholar 

  63. 63.

    Iwasaki M, Kuwata T, Yamazaki Y, et al. Identification of cooperative genes forNUP98-HOXA9 in myeloid leukemogenesis using a mouse model.Blood. 2004;104:1127–1136.

    Article  CAS  Google Scholar 

  64. 64.

    Grisolano JL, Sclar GM, Ley TJ. Early myeloid cell-specific expression of the human cathepsin G gene in transgenic mice.Proc Natl Acad Sci USA. 1994;91:8989–8993.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. 65.

    Grisolano JL, Wesselschmidt RL, Pelicci PG, Ley TJ. Altered myeloid development and acute leukemia in transgenic mice expressing PML-RARa under control of cathepsin G regulatory sequences.Blood. 1997;89:376–387.

    PubMed  CAS  Google Scholar 

  66. 66.

    Jenkins NA, Copeland NG, Taylor BA, Bedigian HG, Lee BK. Ecotropic murine leukemia virus DNA content of normal and lym- phomatous tissues of BXH-2 recombinant inbred mice.J. Virol. 1982;42:379–388.

    PubMed  PubMed Central  CAS  Google Scholar 

  67. 67.

    Copeland NG, Jenkins NA. Myeloid leukemia: disease genes and mouse models. In: Hiai H, Hino O, eds.Animal Models of Cancer Predisposition Syndromes. Basel, Switzerland: Karger; 1999:53–63.

    Google Scholar 

  68. 68.

    Mikkers H, Berns A. Retroviral insertional mutagenesis: tagging cancer pathways.Adv Cancer Res. 2003;88:53–99.

    PubMed  CAS  Google Scholar 

  69. 69.

    Li J, Shen H, Himmel KL, et al. Leukaemia disease gene: large- scale cloning and pathway predictions.Nat Genet. 1999;23:348–353.

    Article  PubMed  CAS  Google Scholar 

  70. 70.

    Suzuki T, Shen H, Akagi K, et al. New genes involved in cancer identified by retroviral tagging.Nat Genet. 2002;32:166–174.

    Article  CAS  Google Scholar 

  71. 71.

    Milisav I. Dynein and dynein-related genes.Cell Motil Cytoskeleton. 1998;39:261–272.

    Article  CAS  Google Scholar 

  72. 72.

    Puthalakath H, Huang DC, O’Reilly LA, King SM, Strasser A. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex.Mol Cell. 1999;3:287–2966.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. 73.

    Vadlamudi RK, Bagheri-Yarmand R, Yang Z, et al. Dynein light chain 1, a p21-activated kinase 1-interacting substrate, promotes cancerous phenotypes.Cancer Cell. 2004;5:575–585.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. 74.

    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 NatlAcad Sci USA. 2002;99:7622–7627.

    Article  CAS  Google Scholar 

  75. 75.

    Mayotte N, Roy D-C, Yao J, Kroon E, Sauvageau G. Oncogenic interaction betweenBCR-ABL andNUP98-HOXA9 demonstrated by the use of an in vitro purging culture system.Blood. 2002;100:4177–4184.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. 76.

    Yamamoto K, Nakamura Y, Saito K, Furusawa S. Expression of theNUP98/HOXA9 fusion transcript in the blast crisis of Philadelphia chromosome-positive chronic myelogenous leukaemia with t(7;11) (p15;p15).Br J Haematol. 2000;109:423–426.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. 77.

    Ahuja HG, Popplewell L, Tcheurekdijian L, Slovak ML.NUP98 gene rearrangements and the clonal evolution of chronic myelogenous leukemia.Genes Chromosomes Cancer. 2001;30:410–415.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. 78.

    Look AT. Oncogenic transcription factors in the human acute leukemias.Science. 1997;278:1059–1064.

    Article  PubMed  CAS  Google Scholar 

  79. 79.

    Graux C, Cools J, Melotte C, et al. Fusion ofNUP214 toABL1 on amplified episomes in T-cell acute lymphoblastic leukemia.Nat ience. 1997;278:1059–1064.

    Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Takuro Nakamura.

About this article

Cite this article

Nakamura, T. NUP98 Fusion in Human Leukemia: Dysregulation of the Nuclear Pore and Homeodomain Proteins. Int J Hematol 82, 21–27 (2005). https://doi.org/10.1532/IJH97.04160

Download citation

Key words

  • NUP98
  • HOX
  • Nucleoporin
  • Nuclear pore complex
  • Cooperative gene