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On the Effects of Leukemogenic Nucleoporin Fusion Proteins on Nucleocytoplasmic Transport and Gene Expression

  • Nuno Martins
  • Adélia Mendes
  • Birthe Fahrenkrog
Chapter
Part of the Nucleic Acids and Molecular Biology book series (NUCLEIC, volume 33)

Abstract

Chromosomal translocations involving NUP98 and NUP214 genes are recurrently reported in hematologic neoplasms of aggressive nature. Such genomic aberrations encode fusion proteins that conserve the phenylalanine-glycine (FG) domain of the respective nucleoporin fused to a wide range of partners. A common feature of most leukemia patients expressing Nup98 or Nup214 fusion proteins is the upregulation of HOX clustered genes. Consequently, cells expressing Nup98 or Nup214 fusion proteins exhibit perturbed cellular functions that translate in increased self-renewal capacity and impaired cellular differentiation. Given the high affinity of both nucleoporins to several nuclear transport receptors (NTRs) and particularly to the protein export receptor CRM1, both Nup98 and Nup214 are key players in the process of nucleocytoplasmic transport of macromolecules across the nuclear pore complex. Besides their role in nuclear transport, Nup98 and Nup214 participate in a myriad of cellular processes, such as epigenetic memory, mitotic regulation, and gene expression. In this chapter, we summarize the current findings on the effects of Nup98 and Nup214 fusions on cell behavior and their role in the etiology of leukemia.

Keywords

CRM1 HOX genes Leukemia Nucleoporin Nup98 Nup214 Oncogenic fusions 

List of Abbreviations

AML

Acute myeloid leukemia

APC/C

Anaphase-promoting complex/cyclosome

AUL

Acute undifferentiated leukemia

circRNA

Circular RNA

f-circRNA

Fused circular RNA

FG

Phenylalanine-glycine

GLEBS

Gle2-binding sequence

GLFG

Glycine-leucine-phenylalanine-glycine

HAT

Histone acetyltransferase

HD

Homeodomain

HOX

Homeobox gene

HPCs

Hematopoietic progenitor cells

INHAT

Inhibitor of acetyltransferases complex

LMB

Leptomycin B

mRNPs

Messenger ribonucleoproteins

NE

Nuclear envelope

NES

Nuclear export signal

NPC

Nuclear pore complex

NTR

Nuclear transport receptor

PEST

Proline-glutamic acid-serine-threonine

PHD

Plant homeodomain

PML

Promyelocytic leukemia

SET

Suppressor of variegation enhancer of zeste-trithorax

T-ALL

T-cell acute lymphoblastic leukemia

Notes

Acknowledgments

This work was supported by grants from the Fonds National de la Recherche Scientifique (FNRS; grant numbers T.0082.14, J.0136.16, and FRIA 16752) and by the Université Libre de Bruxelles.

References

  1. Abe A, Yamamoto Y, Iba S, Okamoto A, Tokuda M, Inaguma Y, Yanada M, Morishima S, Kanie T, Tsuzuki M, Akatsuka Y, Mizuta S, Okamoto M, Kameyama T, Mayeda A, Emi N (2015) NUP214-RAC1 and RAC1-COL12A1 fusion in complex variant translocations involving chromosomes 6, 7 and 9 in an acute myeloid leukemia case with DEK-NUP214. Cytogenet Genome Res 146(4):279–284.  https://doi.org/10.1159/000441464CrossRefPubMedGoogle Scholar
  2. Ageberg M, Drott K, Olofsson T, Gullberg U, Lindmark A (2008) Identification of a novel and myeloid specific role of the leukemia-associated fusion protein DEK-NUP214 leading to increased protein synthesis. Genes Chromosom Cancer 47(4):276–287.  https://doi.org/10.1002/gcc.20531CrossRefPubMedGoogle Scholar
  3. Ahuja HG, Felix CA, Aplan PD (1999) The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion. Blood 94(9):3258–3261PubMedGoogle Scholar
  4. Ahuja HG, Hong J, Aplan PD, Tcheurekdjian L, Forman SJ, Slovak ML (2000) 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 60(22):6227–6229PubMedGoogle Scholar
  5. Akiki S, Dyer SA, Grimwade D, Ivey A, Abou-Zeid N, Borrow J, Jeffries S, Caddick J, Newell H, Begum S, Tawana K, Mason J, Velangi M, Griffiths M (2013) NUP98-NSD1 fusion in association with FLT3-ITD mutation identifies a prognostically relevant subgroup of pediatric acute myeloid leukemia patients suitable for monitoring by real time quantitative PCR. Genes Chromosom Cancer 52(11):1053–1064.  https://doi.org/10.1002/gcc.22100CrossRefPubMedGoogle Scholar
  6. Alber F, Dokudovskaya S, Veenhoff LM, Zhang W, Kipper J, Devos D, Suprapto A, Karni-Schmidt O, Williams R, Chait BT, Sali A, Rout MP (2007) The molecular architecture of the nuclear pore complex. Nature 450(7170):695–701.  https://doi.org/10.1038/nature06405CrossRefPubMedGoogle Scholar
  7. Aoto T, Saitoh N, Ichimura T, Niwa H, Nakao M (2006) Nuclear and chromatin reorganization in the MHC-Oct3/4 locus at developmental phases of embryonic stem cell differentiation. Dev Biol 298(2):354–367.  https://doi.org/10.1016/j.ydbio.2006.04.450CrossRefPubMedGoogle Scholar
  8. Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, Evantal N, Memczak S, Rajewsky N, Kadener S (2014) circRNA biogenesis competes with pre-mRNA splicing. Mol Cell 56(1):55–66.  https://doi.org/10.1016/j.molcel.2014.08.019CrossRefPubMedGoogle Scholar
  9. Askjaer P, Bachi A, Wilm M, Bischoff FR, Weeks DL, Ogniewski V, Ohno M, Niehrs C, Kjems J, Mattaj IW, Fornerod M (1999) RanGTP-regulated interactions of CRM1 with nucleoporins and a shuttling DEAD-box helicase. Mol Cell Biol 19(9):6276–6285CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bai XT, Gu BW, Yin T, Niu C, Xi XD, Zhang J, Chen Z, Chen SJ (2006) Trans-repressive effect of NUP98-PMX1 on PMX1-regulated c-FOS gene through recruitment of histone deacetylase 1 by FG repeats. Cancer Res 66(9):4584–4590CrossRefPubMedGoogle Scholar
  11. Baker DJ, Chen J, van Deursen JM (2005) The mitotic checkpoint in cancer and aging: what have mice taught us? Curr Opin Cell Biol 17(6):583–589.  https://doi.org/10.1016/j.ceb.2005.09.011CrossRefPubMedGoogle Scholar
  12. Baker DJ, Dawlaty MM, Galardy P, van Deursen JM (2007) Mitotic regulation of the anaphase-promoting complex. Cell Mol Life Sci 64(5):589–600.  https://doi.org/10.1007/s00018-007-6443-1CrossRefPubMedGoogle Scholar
  13. Barrett SP, Wang PL, Salzman J (2015) Circular RNA biogenesis can proceed through an exon-containing lariat precursor. eLife 4:e07540.  https://doi.org/10.7554/eLife.07540CrossRefPubMedPubMedCentralGoogle Scholar
  14. Bei L, Lu Y, Eklund EA (2005) HOXA9 activates transcription of the gene encoding gp91Phox during myeloid differentiation. J Biol Chem 280(13):12359–12370CrossRefPubMedGoogle Scholar
  15. Ben Abdelali R, Roggy A, Leguay T, Cieslak A, Renneville A, Touzart A, Banos A, Randriamalala E, Caillot D, Lioure B, Devidas A, Mossafa H, Preudhomme C, Ifrah N, Dombret H, Macintyre E, Asnafi V (2014) SET-NUP214 is a recurrent γδ lineage-specific fusion transcript associated with corticosteroid/chemotherapy resistance in adult T-ALL. Blood 123(12):1860–1863.  https://doi.org/10.1182/blood-2013-08-521518CrossRefPubMedGoogle Scholar
  16. Bernad R, Engelsma D, Sanderson H, Pickersgill H, Fornerod M (2006) Nup214-Nup88 nucleoporin subcomplex is required for CRM1-mediated 60 S preribosomal nuclear export. J Biol Chem 281(28):19378–19386.  https://doi.org/10.1074/jbc.M512585200CrossRefPubMedGoogle Scholar
  17. Boer J, Bonten-Surtel J, Grosveld G (1998) Overexpression of the nucleoporin CAN/NUP214 induces growth arrest, nucleocytoplasmic transport defects, and apoptosis. Mol Cell Biol 18(3):1236–1247CrossRefPubMedPubMedCentralGoogle Scholar
  18. Borrow J, Shearman AM, Stanton VP, Jr., Becher R, Collins T, Williams AJ, Dube I, Katz F, Kwong YL, Morris C, Ohyashiki K, Toyama K, Rowley J, Housman DE (1996) The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nat Genet 12 (2):159-167. doi: https://doi.org/10.1038/ng0296-159CrossRefPubMedGoogle Scholar
  19. Broxmeyer HE, Kappes F, Mor-Vaknin N, Legendre M, Kinzfogl J, Cooper S, Hangoc G, Markovitz DM (2012) DEK regulates hematopoietic stem engraftment and progenitor cell proliferation. Stem Cells Dev 21(9):1449–1454.  https://doi.org/10.1089/scd.2011.0451CrossRefPubMedGoogle Scholar
  20. Burke B, Stewart CL (2013) The nuclear lamins: flexibility in function. Nat Rev Mol Cell Biol 14(1):13–24CrossRefPubMedGoogle Scholar
  21. Burmeister T, Gokbuget N, Reinhardt R, Rieder H, Hoelzer D, Schwartz S (2006) NUP214-ABL1 in adult T-ALL: the GMALL study group experience. Blood 108(10):3556–3559.  https://doi.org/10.1182/blood-2006-04-014514CrossRefPubMedGoogle Scholar
  22. Butin-Israeli V, Adam SA, Goldman AE, Goldman RD (2012) Nuclear lamin functions and disease. Trends Genet 28(9):464–471.  https://doi.org/10.1016/j.tig.2012.06.001CrossRefPubMedPubMedCentralGoogle Scholar
  23. Butler JT, Hall LL, Smith KP, Lawrence JB (2009) Changing nuclear landscape and unique PML structures during early epigenetic transitions of human embryonic stem cells. J Cell Biochem 107(4):609–621.  https://doi.org/10.1002/jcb.22183CrossRefPubMedPubMedCentralGoogle Scholar
  24. Calvo KR, Sykes DB, Pasillas MP, Kamps MP (2002) Nup98-HoxA9 immortalizes myeloid progenitors, 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 21(27):4247–4256.  https://doi.org/10.1038/sj.onc.1205516CrossRefPubMedGoogle Scholar
  25. Capelson M, Liang Y, Schulte R, Mair W, Wagner U, Hetzer MW (2010) Chromatin-bound nuclear pore components regulate gene expression in higher eukaryotes. Cell 140(3):372–383.  https://doi.org/10.1016/j.cell.2009.12.054CrossRefPubMedPubMedCentralGoogle Scholar
  26. Casas S, Nagy B, Elonen E, Aventin A, Larramendy ML, Sierra J, Ruutu T, Knuutila S (2003) Aberrant expression of HOXA9, DEK, CBL and CSF1R in acute myeloid leukemia. Leuk Lymphoma 44(11):1935–1941.  https://doi.org/10.1080/1042819031000119299CrossRefPubMedGoogle Scholar
  27. Cervoni N, Detich N, Seo SB, Chakravarti D, Szyf M (2002) The oncoprotein Set/TAF-1β, an inhibitor of histone acetyltransferase, inhibits active demethylation of DNA, integrating DNA methylation and transcriptional silencing. J Biol Chem 277(28):25026–25031.  https://doi.org/10.1074/jbc.M202256200CrossRefPubMedGoogle Scholar
  28. Chatel G, Desai SH, Mattheyses AL, Powers MA, Fahrenkrog B (2012) Domain topology of nucleoporin Nup98 within the nuclear pore complex. J Struct Biol 177(1):81–89.  https://doi.org/10.1016/j.jsb.2011.11.004CrossRefPubMedGoogle Scholar
  29. Chou WC, Chen CY, Hou HA, Lin LI, Tang JL, Yao M, Tsay W, Ko BS, Wu SJ, Huang SY, Hsu SC, Chen YC, Huang YN, Tseng MH, Huang CF, Tien HF (2009) Acute myeloid leukemia bearing t(7;11)(p15;p15) is a distinct cytogenetic entity with poor outcome and a distinct mutation profile: comparative analysis of 493 adult patients. Leukemia 23(7):1303–1310.  https://doi.org/10.1038/leu.2009.25CrossRefPubMedGoogle Scholar
  30. Cilloni D, Saglio G (2012) Molecular pathways: BCR-ABL. Clin Cancer Res 18(4):930–937.  https://doi.org/10.1158/1078-0432.CCR-10-1613CrossRefPubMedGoogle Scholar
  31. Clarke S, O’Reilly J, Romeo G, Cooney J (2011) NUP214-ABL1 positive T-cell acute lymphoblastic leukemia patient shows an initial favorable response to imatinib therapy post relapse. Leuk Res 35(7):e131–e133.  https://doi.org/10.1016/j.leukres.2011.03.025CrossRefPubMedGoogle Scholar
  32. Collas P, Lund EG, Oldenburg AR (2014) Closing the (nuclear) envelope on the genome: how nuclear lamins interact with promoters and modulate gene expression. BioEssays 36(1):75–83.  https://doi.org/10.1002/bies.201300138CrossRefPubMedGoogle Scholar
  33. Conway AE, Haldeman JM, Wechsler DS, Lavau CP (2015) A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias. Leukemia 29(2):423–432.  https://doi.org/10.1038/leu.2014.221CrossRefPubMedGoogle Scholar
  34. Dai W, Wang Q, Liu T, Swamy M, Fang Y, Xie S, Mahmood R, Yang YM, Xu M, Rao CV (2004) Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res 64(2):440–445CrossRefPubMedGoogle Scholar
  35. De Keersmaecker K, Rocnik JL, Bernad R, Lee BH, Leeman D, Gielen O, Verachtert H, Folens C, Munck S, Marynen P, Fornerod M, Gilliland DG, Cools J (2008a) Kinase activation and transformation by NUP214-ABL1 is dependent on the context of the nuclear pore. Mol Cell 31(1):134–142CrossRefPubMedGoogle Scholar
  36. De Keersmaecker K, Versele M, Cools J, Superti-Furga G, Hantschel O (2008b) Intrinsic differences between the catalytic properties of the oncogenic NUP214-ABL1 and BCR-ABL1 fusion protein kinases. Leukemia 22(12):2208–2216.  https://doi.org/10.1038/leu.2008.242CrossRefPubMedGoogle Scholar
  37. de Klein A, van Kessel AG, Grosveld G, Bartram CR, Hagemeijer A, Bootsma D, Spurr NK, Heisterkamp N, Groffen J, Stephenson JR (1982) A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 300(5894):765–767CrossRefPubMedGoogle Scholar
  38. Dechat T, Gesson K, Foisner R (2010) Lamina-independent lamins in the nuclear interior serve important functions. Cold Spring Harb Symp Quant Biol 75:533–543.  https://doi.org/10.1101/sqb.2010.75.018CrossRefPubMedGoogle Scholar
  39. Denning DP, Patel SS, Uversky V, Fink AL, Rexach M (2003) Disorder in the nuclear pore complex: the FG repeat regions of nucleoporins are natively unfolded. Proc Natl Acad Sci USA 100(5):2450–2455CrossRefPubMedGoogle Scholar
  40. Devos D, Dokudovskaya S, Williams R, Alber F, Eswar N, Chait BT, Rout MP, Sali A (2006) Simple fold composition and modular architecture of the nuclear pore complex. Proc Natl Acad Sci US A 103(7):2172–2177CrossRefGoogle Scholar
  41. Dultz E, Zanin E, Wurzenberger C, Braun M, Rabut G, Sironi L, Ellenberg J (2008) Systematic kinetic analysis of mitotic dis- and reassembly of the nuclear pore in living cells. J Cell Biol 180(5):857–865CrossRefPubMedPubMedCentralGoogle Scholar
  42. Duployez N, Grzych G, Ducourneau B, Alarcon Fuentes M, Grardel N, Boyer T, Abou Chahla W, Bruno B, Nelken B, Clappier E, Preudhomme C (2016) NUP214-ABL1 fusion defines a rare subtype of B-cell precursor acute lymphoblastic leukemia that could benefit from tyrosine kinase inhibitors. Haematologica 101(4):e133–e134.  https://doi.org/10.3324/haematol.2015.136499CrossRefPubMedPubMedCentralGoogle Scholar
  43. Fahrenkrog B (2014) Nucleoporin gene fusions and hematopoietic malignancies. New J Sci 2014:18.  https://doi.org/10.1155/2014/468306CrossRefGoogle Scholar
  44. Fahrenkrog B, Martinelli V, Nilles N, Fruhmann G, Chatel G, Juge S, Sauder U, Di Giacomo D, Mecucci C, Schwaller J (2016) Expression of leukemia-associated Nup98 fusion proteins generates an aberrant nuclear envelope phenotype. PLoS One 11(3):e0152321.  https://doi.org/10.1371/journal.pone.0152321CrossRefPubMedPubMedCentralGoogle Scholar
  45. Fornerod M, Ohno M, Yoshida M, Mattaj IW (1997) CRM1 is an export receptor for leucine-rich nuclear export signals. Cell 90(6):1051–1060CrossRefPubMedGoogle Scholar
  46. Fujino T, Suzuki A, Ito Y, Ohyashiki K, Hatano Y, Miura I, Nakamura T (2002) 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 99(4):1428–1433CrossRefPubMedGoogle Scholar
  47. Funasaka T, Nakano H, Wu Y, Hashizume C, Gu L, Nakamura T, Wang W, Zhou P, Moore MA, Sato H, Wong RW (2011) RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesis. Cell Cycle 10(9):1456–1467.  https://doi.org/10.4161/cc.10.9.15494CrossRefPubMedGoogle Scholar
  48. Gamble MJ, Erdjument-Bromage H, Tempst P, Freedman LP, Fisher RP (2005) The histone chaperone TAF-I/SET/INHAT is required for transcription in vitro of chromatin templates. Mol Cell Biol 25(2):797–807.  https://doi.org/10.1128/MCB.25.2.797-807.2005CrossRefPubMedPubMedCentralGoogle Scholar
  49. Gerace L, Huber MD (2012) Nuclear lamina at the crossroads of the cytoplasm and nucleus. J Struct Biol 177(1):24–31.  https://doi.org/10.1016/j.jsb.2011.11.007CrossRefPubMedGoogle Scholar
  50. Gervais C, Mauvieux L, Perrusson N, Helias C, Struski S, Leymarie V, Lioure B, Lessard M (2005) 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 19(1):145–148.  https://doi.org/10.1038/sj.leu.2403565CrossRefPubMedGoogle Scholar
  51. Ghannam G, Takeda A, Camarata T, Moore MA, Viale A, Yaseen NR (2004) The oncogene Nup98-HOXA9 induces gene transcription in myeloid cells. J Biol Chem 279(2):866–875.  https://doi.org/10.1074/jbc.M307280200CrossRefPubMedGoogle Scholar
  52. Ghavami A, van der Giessen E, Onck PR (2016) Energetics of transport through the nuclear pore complex. PLoS One 11(2):e0148876.  https://doi.org/10.1371/journal.pone.0148876CrossRefPubMedPubMedCentralGoogle Scholar
  53. Gorello P, Brandimarte L, La Starza R, Pierini V, Bury L, Rosati R, Martelli MF, Vandenberghe P, Wlodarska I, Mecucci C (2008) t(3;11)(q12;p15)/NUP98-LOC348801 fusion transcript in acute myeloid leukemia. Haematologica 93(9): 1398–1401CrossRefPubMedGoogle Scholar
  54. Gorello P, La Starza R, Di Giacomo D, Messina M, Puzzolo MC, Crescenzi B, Santoro A, Chiaretti S, Mecucci C (2010) SQSTM1-NUP214: a new gene fusion in adult T-cell acute lymphoblastic leukemia. Haematologica 95(12):2161–2163.  https://doi.org/10.3324/haematol.2010.029769CrossRefPubMedPubMedCentralGoogle Scholar
  55. Gough SM, Slape CI, Aplan PD (2011) NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights. Blood 118(24):6247–6257.  https://doi.org/10.1182/blood-2011-07-328880CrossRefPubMedPubMedCentralGoogle Scholar
  56. Graux C, Cools J, Melotte C, Quentmeier H, Ferrando A, Levine R, Vermeesch JR, Stul M, Dutta B, Boeckx N, Bosly A, Heimann P, Uyttebroeck A, Mentens N, Somers R, MacLeod RA, Drexler HG, Look AT, Gilliland DG, Michaux L, Vandenberghe P, Wlodarska I, Marynen P, Hagemeijer A (2004) Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet 36(10):1084–1089.  https://doi.org/10.1038/ng1425CrossRefPubMedGoogle Scholar
  57. Griffis ER, Altan N, Lippincott-Schwartz J, Powers MA (2002) Nup98 is a mobile nucleoporin with transcription-dependent dynamics. Mol Biol Cell 13(4):1282–1297CrossRefPubMedPubMedCentralGoogle Scholar
  58. Griffis ER, Xu S, Powers MA (2003) Nup98 localizes to both nuclear and cytoplasmic sides of the nuclear pore and binds to two distinct nucleoporin subcomplexes. Mol Biol Cell 14(2):600–610.  https://doi.org/10.1091/mbc.E02-09-0582CrossRefPubMedPubMedCentralGoogle Scholar
  59. Griffis ER, Craige B, Dimaano C, Ullman KS, Powers MA (2004) Distinct functional domains within nucleoporins Nup153 and Nup98 mediate transcription-dependent mobility. Mol Biol Cell 15(4):1991–2002.  https://doi.org/10.1091/mbc.E03-10-0743CrossRefPubMedPubMedCentralGoogle Scholar
  60. Guarnerio J, Bezzi M, Jeong Jong C, Paffenholz Stella V, Berry K, Naldini Matteo M, Lo-Coco F, Tay Y, Beck Andrew H, Pandolfi Pier P (2016) Oncogenic role of fusion-circRNAs derived from cancer-associated chromosomal translocations. Cell 165(2):289–302.  https://doi.org/10.1016/j.cell.2016.03.020CrossRefPubMedGoogle Scholar
  61. Gurevich RM, Aplan PD, Humphries RK (2004) NUP98-topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation. Blood 104(4):1127CrossRefPubMedGoogle Scholar
  62. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495(7441):384–388. http://www.nature.com/nature/journal/v495/n7441/abs/nature11993.html - supplementary-informationCrossRefPubMedGoogle Scholar
  63. Hickey FB, Cotter TG (2006) BCR-ABL regulates phosphatidylinositol 3-kinase-p110γ transcription and activation and is required for proliferation and drug resistance. J Biol Chem 281(5):2441–2450.  https://doi.org/10.1074/jbc.M511173200CrossRefPubMedGoogle Scholar
  64. Hirose K, Abramovich C, Argiropoulos B, Humphries RK (2008) Leukemogenic properties of NUP98-PMX1 are linked to NUP98 and homeodomain sequence functions but not to binding properties of PMX1 to serum response factor. Oncogene 27(46):6056–6067.  https://doi.org/10.1038/onc.2008.210CrossRefPubMedGoogle Scholar
  65. Hollink IHIM, van den Heuvel-Eibrink MM, Arentsen-Peters STCJM, Pratcorona M, Abbas S, Kuipers JE, van Galen JF, Beverloo HB, Sonneveld E, Kaspers G-JJL, Trka J, Baruchel A, Zimmermann M, Creutzig U, Reinhardt D, Pieters R, Valk PJM, Zwaan CM (2011) NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. Blood 118 (13):3645CrossRefPubMedGoogle Scholar
  66. Hülsmann BB, Labokha Aksana A, Görlich D (2012) The permeability of reconstituted nuclear pores provides direct evidence for the selective phase model. Cell 150(4):738–751.  https://doi.org/10.1016/j.cell.2012.07.019CrossRefPubMedGoogle Scholar
  67. Hussey DJ, Dobrovic A (2002) Recurrent coiled-coil motifs in NUP98 fusion partners provide a clue to leukemogenesis. Blood 99(3):1097CrossRefPubMedGoogle Scholar
  68. Hussey DJ, Nicola M, Moore S, Peters GB, Dobrovic A (1999) The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia. Blood 94(6):2072–2079PubMedGoogle Scholar
  69. Hutten S, Kehlenbach RH (2006) Nup214 is required for CRM1-dependent nuclear protein export in vivo. Mol Cell Biol 26(18):6772–6785CrossRefPubMedPubMedCentralGoogle Scholar
  70. Hutten S, Kehlenbach RH (2007) CRM1-mediated nuclear export: to the pore and beyond. Trends Cell Biol 17(4):193–201.  https://doi.org/10.1016/j.tcb.2007.02.003CrossRefPubMedPubMedCentralGoogle Scholar
  71. Ichijo T, Chrousos GP, Kino T (2008) Activated glucocorticoid receptor interacts with the INHAT component Set/TAF-Ibeta and releases it from a glucocorticoid-responsive gene promoter, relieving repression: implications for the pathogenesis of glucocorticoid resistance in acute undifferentiated leukemia with Set-Can translocation. Mol Cell Endocrinol 283(1–2):19–31.  https://doi.org/10.1016/j.mce.2007.10.014CrossRefPubMedGoogle Scholar
  72. Ishikawa M, Yagasaki F, Okamura D, Maeda T, Sugahara Y, Jinnai I, Bessho M (2007) A novel gene, ANKRD28 on 3p25, is fused with NUP98 on 11p15 in a cryptic 3-way translocation of t(3;5;11)(p25;q35;p15) in an adult patient with myelodysplastic syndrome/acute myelogenous leukemia. Int J Hematol 86(3):238–245.  https://doi.org/10.1532/IJH97.07054CrossRefPubMedGoogle Scholar
  73. Jaju RJ, Fidler C, Haas OA, Strickson AJ, Watkins F, Clark K, Cross NC, Cheng JF, Aplan PD, Kearney L, Boultwood J, Wainscoat JS (2001) A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Blood 98(4):1264–1267CrossRefPubMedGoogle Scholar
  74. Jankovic D, Gorello P, Liu T, Ehret S, La Starza R, Desjobert C, Baty F, Brutsche M, Jayaraman P-S, Santoro A, Mecucci C, Schwaller J (2008) Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia. Blood 111(12):5672CrossRefPubMedGoogle Scholar
  75. Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, Marzluff WF, Sharpless NE (2013) Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19(2):141–157.  https://doi.org/10.1261/rna.035667.112CrossRefPubMedPubMedCentralGoogle Scholar
  76. Jeganathan KB, Malureanu L, van Deursen JM (2005) The Rae1-Nup98 complex prevents aneuploidy by inhibiting securin degradation. Nature 438(7070):1036–1039CrossRefPubMedGoogle Scholar
  77. Jeganathan KB, Baker DJ, van Deursen JM (2006) Securin associates with APCCdh1 in prometaphase but its destruction is delayed by Rae1 and Nup98 until the metaphase/anaphase transition. Cell Cycle 5(4):366–370CrossRefPubMedGoogle Scholar
  78. Kaltenbach S, Soler G, Barin C, Gervais C, Bernard OA, Penard-Lacronique V, Romana SP (2010) NUP98-MLL fusion in human acute myeloblastic leukemia. Blood 116(13):2332CrossRefPubMedGoogle Scholar
  79. Kalverda B, Pickersgill H, Shloma VV, Fornerod M (2010) Nucleoporins directly stimulate expression of developmental and cell-cycle genes inside the nucleoplasm. Cell 140(3):360–371.  https://doi.org/10.1016/j.cell.2010.01.011CrossRefPubMedGoogle Scholar
  80. Kandilci A, Mientjes E, Grosveld G (2004) Effects of SET and SET-CAN on the differentiation of the human promonocytic cell line U937. Leukemia 18(2):337–340.  https://doi.org/10.1038/sj.leu.2403227CrossRefPubMedGoogle Scholar
  81. Kappes F, Burger K, Baack M, Fackelmayer FO, Gruss C (2001) Subcellular localization of the human proto-oncogene protein DEK. J Biol Chem 276(28):26317–26323.  https://doi.org/10.1074/jbc.M100162200CrossRefPubMedGoogle Scholar
  82. Kasper LH, Brindle PK, Schnabel CA, Pritchard CEJ, Cleary ML, van Deursen JMA (1999) CREB binding protein interacts with nucleoporin-specific FG Repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. Mol Cell Biol 19(1):764–776CrossRefPubMedPubMedCentralGoogle Scholar
  83. Kehlenbach RH, Dickmanns A, Kehlenbach A, Guan T, Gerace L (1999) A role for RanBP1 in the release of CRM1 from the nuclear pore complex in a terminal step of nuclear export. J Cell Biol 145(4):645–657CrossRefPubMedPubMedCentralGoogle Scholar
  84. Kim J, Lee SG, Song J, Kim SJ, Rha SY, Lee KA, Park TS, Choi JR (2010) Molecular characterization of alternative SET-NUP214 fusion transcripts in a case of acute undifferentiated leukemia. Cancer Genet Cytogenet 201(2):73–80.  https://doi.org/10.1016/j.cancergencyto.2010.05.010CrossRefPubMedGoogle Scholar
  85. Kim JY, Kim KB, Son HJ, Chae YC, Oh ST, Kim DW, Pak JH, Seo SB (2012) H3K27 methylation and H3S28 phosphorylation-dependent transcriptional regulation by INHAT subunit SET/TAF-Ibeta. FEBS Lett 586(19):3159–3165.  https://doi.org/10.1016/j.febslet.2012.06.026CrossRefPubMedGoogle Scholar
  86. Kirli K, Karaca S, Dehne HJ, Samwer M, Pan KT, Lenz C, Urlaub H, Gorlich D (2015) A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 4.  https://doi.org/10.7554/eLife.11466
  87. Kosinski J, Mosalaganti S, von Appen A, Teimer R, DiGuilio AL, Wan W, Bui KH, Hagen WJ, Briggs JA, Glavy JS, Hurt E, Beck M (2016) Molecular architecture of the inner ring scaffold of the human nuclear pore complex. Science 352(6283):363–365.  https://doi.org/10.1126/science.aaf0643CrossRefPubMedGoogle Scholar
  88. Kroon E, Thorsteinsdottir U, Mayotte N, Nakamura T, Sauvageau G (2001) NUP98–HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice. EMBO J 20(3):350CrossRefPubMedPubMedCentralGoogle Scholar
  89. Lahortiga I, Vizmanos JL, Agirre X, Vazquez I, Cigudosa JC, Larrayoz MJ, Sala F, Gorosquieta A, Perez-Equiza K, Calasanz MJ, Odero MD (2003) 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 63(12):3079–3083PubMedGoogle Scholar
  90. Laurell E, Kutay U (2011) Dismantling the NPC permeability barrier at the onset of mitosis. Cell Cycle 10(14):2243–2245.  https://doi.org/10.4161/cc.10.14.16195CrossRefPubMedGoogle Scholar
  91. Laurell E, Beck K, Krupina K, Theerthagiri G, Bodenmiller B, Horvath P, Aebersold R, Antonin W, Kutay U (2011) Phosphorylation of Nup98 by multiple kinases is crucial for NPC disassembly during mitotic entry. Cell 144(4):539–550.  https://doi.org/10.1016/j.cell.2011.01.012CrossRefPubMedGoogle Scholar
  92. Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, Zhong G, Yu B, Hu W, Dai L, Zhu P, Chang Z, Wu Q, Zhao Y, Jia Y, Xu P, Liu H, Shan G (2015) Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol 22(3):256–264.  https://doi.org/10.1038/nsmb.2959. http://www.nature.com/nsmb/journal/v22/n3/abs/nsmb.2959.html-supplementary-informationCrossRefGoogle Scholar
  93. Liang Y, Franks TM, Marchetto MC, Gage FH, Hetzer MW (2013) Dynamic association of NUP98 with the human genome. PLoS Genet 9(2):e1003308.  https://doi.org/10.1371/journal.pgen.1003308CrossRefPubMedPubMedCentralGoogle Scholar
  94. Light WH, Freaney J, Sood V, Thompson A, D'Urso A, Horvath CM, Brickner JH (2013) A conserved role for human Nup98 in altering chromatin structure and promoting epigenetic transcriptional memory. PLoS Biol 11(3):e1001524.  https://doi.org/10.1371/journal.pbio.1001524CrossRefPubMedPubMedCentralGoogle Scholar
  95. Lim RY, Fahrenkrog B (2006) The nuclear pore complex up close. Curr Opin Cell Biol 18(3):342–347CrossRefPubMedGoogle Scholar
  96. Lim RY, Huang NP, Koser J, Deng J, Lau KH, Schwarz-Herion K, Fahrenkrog B, Aebi U (2006) Flexible phenylalanine-glycine nucleoporins as entropic barriers to nucleocytoplasmic transport. Proc Natl Acad Sci USA 103(25):9512–9517.  https://doi.org/10.1073/pnas.0603521103CrossRefPubMedGoogle Scholar
  97. Lim RY, Aebi U, Fahrenkrog B (2008) Towards reconciling structure and function in the nuclear pore complex. Histochem Cell Biol 129(2):105–116CrossRefPubMedPubMedCentralGoogle Scholar
  98. Lisboa S, Cerveira N, Bizarro S, Correia C, Vieira J, Torres L, Mariz JM, Teixeira MR (2013) POU1F1 is a novel fusion partner of NUP98 in acute myeloid leukemia with t(3;11)(p11;p15). Mol Cancer 12(1):5.  https://doi.org/10.1186/1476-4598-12-5CrossRefPubMedPubMedCentralGoogle Scholar
  99. Liu F, Gao L, Jing Y, Xu YY, Ding Y, Zhou MH, Ma C, Li MY, Sun JZ, Wang LL, Yu L (2013) Detection and clinical significance of gene rearrangements in Chinese patients with adult acute lymphoblastic leukemia. Leuk Lymphoma 54(7):1521–1526.  https://doi.org/10.3109/10428194.2012.754888CrossRefPubMedGoogle Scholar
  100. Logan GE, Mor-Vaknin N, Braunschweig T, Jost E, Schmidt PV, Markovitz DM, Mills KI, Kappes F, Percy MJ (2015) DEK oncogene expression during normal hematopoiesis and in Acute Myeloid Leukemia (AML). Blood Cells Mol Dis 54(1):123–131.  https://doi.org/10.1016/j.bcmd.2014.07.009CrossRefPubMedGoogle Scholar
  101. Loven MA, Muster N, Yates JR, Nardulli AM (2003) A novel estrogen receptor alpha-associated protein, template-activating factor Ibeta, inhibits acetylation and transactivation. Mol Endocrinol 17(1):67–78.  https://doi.org/10.1210/me.2002-0280CrossRefPubMedGoogle Scholar
  102. Lusk CP, King MC (2017) The nucleus: keeping it together by keeping it apart. Curr Opin Cell Biol 44:44–50.  https://doi.org/10.1016/j.ceb.2017.02.001CrossRefPubMedPubMedCentralGoogle Scholar
  103. Matsuoka Y, Takagi M, Ban T, Miyazaki M, Yamamoto T, Kondo Y, Yoneda Y (1999) Identification and characterization of nuclear pore subcomplexes in mitotic extract of human somatic cells. Biochem Biophys Res Commun 254(2):417–423.  https://doi.org/10.1006/bbrc.1998.9953CrossRefPubMedGoogle Scholar
  104. Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, Loewer A, Ziebold U, Landthaler M, Kocks C, le Noble F, Rajewsky N (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495(7441): 333–338. http://www.nature.com/nature/journal/v495/n7441/abs/nature11928.html-supplementary-informationCrossRefPubMedPubMedCentralGoogle Scholar
  105. Miyauchi Y, Sakaguchi N, Okada T, Makishima M, Ozono K, Michigami T (2009) Oncogenic nucleoporin CAN/Nup214 interacts with vitamin D receptor and modulates its function. J Cell Biochem 106(6):1090–1101.  https://doi.org/10.1002/jcb.22101CrossRefPubMedGoogle Scholar
  106. Montpetit B, Thomsen ND, Helmke KJ, Seeliger MA, Berger JM, Weis K (2011) A conserved mechanism of DEAD-box ATPase activation by nucleoporins and InsP6 in mRNA export. Nature 472(7342):238–242.  https://doi.org/10.1038/nature09862CrossRefPubMedPubMedCentralGoogle Scholar
  107. Morchoisne-Bolhy S, Geoffroy MC, Bouhlel IB, Alves A, Auduge N, Baudin X, Van Bortle K, Powers MA, Doye V (2015) Intranuclear dynamics of the Nup107-160 complex. Mol Biol Cell 26(12):2343–2356.  https://doi.org/10.1091/mbc.E15-02-0060CrossRefPubMedPubMedCentralGoogle Scholar
  108. Muto S, Senda M, Akai Y, Sato L, Suzuki T, Nagai R, Senda T, Horikoshi M (2007) Relationship between the structure of SET/TAF-Ibeta/INHAT and its histone chaperone activity. Proc Natl Acad Sci USA 104(11):4285–4290.  https://doi.org/10.1073/pnas.0603762104CrossRefPubMedGoogle Scholar
  109. Nakamura T, Largaespada DA, Lee MP, Johnson LA, Ohyashiki K, Toyama K, Chen SJ, Willman CL, Chen IM, Feinberg AP, Jenkins NA, Copeland NG, Shaughnessy JD, Jr. (1996) Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet 12 (2):154-158. doi: https://doi.org/10.1038/ng0296-154CrossRefPubMedGoogle Scholar
  110. Nakamura T, Yamazaki Y, Hatano Y, Miura I (1999) NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15). Blood 94(2):741–747PubMedGoogle Scholar
  111. Nakao K, Nishino M, Takeuchi K, Iwata M, Kawano A, Arai Y, Ohki M (2000) Fusion of the nucleoporin gene, NUP98, and the putative RNA helicase gene, DZXX10, by inversion 11 (p15q22) chromosome translocation in a patient with etoposide-related myelodysplastic syndrome. Intern Med 39(5):412–415CrossRefPubMedGoogle Scholar
  112. Napetschnig J, Kassube SA, Debler EW, Wong RW, Blobel G, Hoelz A (2009) Structural and functional analysis of the interaction between the nucleoporin Nup214 and the DEAD-box helicase Ddx19. Proc Natl Acad Sci USA 106(9):3089–3094.  https://doi.org/10.1073/pnas.0813267106CrossRefPubMedGoogle Scholar
  113. Nebral K, Schmidt HH, Haas OA, Strehl S (2005) NUP98 is fused to topoisomerase (DNA) IIbeta 180 kDa (TOP2B) in a patient with acute myeloid leukemia with a new t(3;11)(p24;p15). Clin Cancer Res 11(18):6489–6494.  https://doi.org/10.1158/1078-0432.CCR-05-0150CrossRefPubMedGoogle Scholar
  114. Oancea C, Ruster B, Henschler R, Puccetti E, Ruthardt M (2010) The t(6;9) associated DEK/CAN fusion protein targets a population of long-term repopulating hematopoietic stem cells for leukemogenic transformation. Leukemia 24(11):1910–1919.  https://doi.org/10.1038/leu.2010.180CrossRefPubMedGoogle Scholar
  115. Oancea C, Ruster B, Brill B, Roos J, Heinssmann M, Bug G, Mian AA, Guillen NA, Kornblau SM, Henschler R, Ruthardt M (2014) STAT activation status differentiates leukemogenic from non-leukemogenic stem cells in AML and is suppressed by arsenic in t(6;9)-positive AML. Genes Cancer 5(11–12):378–392PubMedPubMedCentralGoogle Scholar
  116. Oka M, Asally M, Yasuda Y, Ogawa Y, Tachibana T, Yoneda Y (2010) The mobile FG nucleoporin Nup98 is a cofactor for Crm1-dependent protein export. Mol Biol Cell 21(11):1885–1896.  https://doi.org/10.1091/mbc.E09-12-1041CrossRefPubMedPubMedCentralGoogle Scholar
  117. Oka M, Mura S, Yamada K, Sangel P, Hirata S, Maehara K, Kawakami K, Tachibana T, Ohkawa Y, Kimura H, Yoneda Y (2016) Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes. eLife 5:e09540.  https://doi.org/10.7554/eLife.09540CrossRefPubMedPubMedCentralGoogle Scholar
  118. Ommen HB, Touzart A, MacIntyre E, Kern W, Haferlach T, Haferlach C, Tobal K, Hokland P, Schnittger S (2015) The kinetics of relapse in DEK-NUP214-positive acute myeloid leukemia patients. Eur J Haematol 95(5):436–441.  https://doi.org/10.1111/ejh.12511CrossRefPubMedGoogle Scholar
  119. Ostronoff F, Othus M, Gerbing RB, Loken MR, Raimondi SC, Hirsch BA, Lange BJ, Petersdorf S, Radich J, Appelbaum FR, Gamis AS, Alonzo TA, Meshinchi S (2014) NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: a COG and SWOG report. Blood 124(15):2400–2407.  https://doi.org/10.1182/blood-2014-04-570929CrossRefPubMedPubMedCentralGoogle Scholar
  120. Ozbek U, Kandilci A, van Baal S, Bonten J, Boyd K, Franken P, Fodde R, Grosveld GC (2007) SET-CAN, the product of the t(9;9) in acute undifferentiated leukemia, causes expansion of early hematopoietic progenitors and hyperproliferation of stomach mucosa in transgenic mice. Am J Pathol 171(2):654–666.  https://doi.org/10.2353/ajpath.2007.060934CrossRefPubMedPubMedCentralGoogle Scholar
  121. Pajerowski JD, Dahl KN, Zhong FL, Sammak PJ, Discher DE (2007) Physical plasticity of the nucleus in stem cell differentiation. Proc Natl Acad Sci USA 104(40):15619–15624.  https://doi.org/10.1073/pnas.0702576104CrossRefPubMedGoogle Scholar
  122. Palmqvist L, Pineault N, Wasslavik C, Humphries RK (2007) Candidate genes for expansion and transformation of hematopoietic stem cells by NUP98-HOX fusion genes. PLoS One 2(8):e768.  https://doi.org/10.1371/journal.pone.0000768CrossRefPubMedPubMedCentralGoogle Scholar
  123. Pan Q, Zhu YJ, Gu BW, Cai X, Bai XT, Yun HY, Zhu J, Chen B, Weng L, Chen Z, Xue YQ, Chen SJ (2007) A new fusion gene NUP98-IQCG identified in an acute T-lymphoid/myeloid leukemia with a t(3;11)(q29q13;p15)del(3)(q29) translocation. Oncogene 27(24):3414–3423. http://www.nature.com/onc/journal/v27/n24/suppinfo/1210999s1.htmlCrossRefPubMedGoogle Scholar
  124. Panagopoulos I, Isaksson M, Billstrom R, Strombeck B, Mitelman F, Johansson B (2003) Fusion of the NUP98 gene and the homeobox gene HOXC13 in acute myeloid leukemia with t(11;12)(p15;q13). Genes Chromosom Cancer 36(1):107–112.  https://doi.org/10.1002/gcc.10139CrossRefPubMedGoogle Scholar
  125. Panagopoulos I, Kerndrup G, Carlsen N, Strombeck B, Isaksson M, Johansson B (2007) Fusion of NUP98 and the SET binding protein 1 (SETBP1) gene in a paediatric acute T cell lymphoblastic leukaemia with t(11;18)(p15;q12). Br J Haematol 136(2):294–296.  https://doi.org/10.1111/j.1365-2141.2006.06410.xCrossRefPubMedGoogle Scholar
  126. Pascual-Garcia P, Jeong J, Capelson M (2014) Nucleoporin Nup98 associates with Trx/MLL and NSL histone-modifying complexes and regulates Hox gene expression. Cell Rep 9(2):433–442.  https://doi.org/10.1016/j.celrep.2014.09.002CrossRefPubMedGoogle Scholar
  127. Paulillo SM, Phillips EM, Koser J, Sauder U, Ullman KS, Powers MA, Fahrenkrog B (2005) Nucleoporin domain topology is linked to the transport status of the nuclear pore complex. J Mol Biol 351(4):784–798CrossRefPubMedGoogle Scholar
  128. Petit A, Ragu C, Della-Valle V, Mozziconacci MJ, Lafage-Pochitaloff M, Soler G, Schluth C, Radford I, Ottolenghi C, Bernard OA, Penard-Lacronique V, Romana SP (2010) NUP98-HMGB3: a novel oncogenic fusion. Leukemia 24(3):654–658.  https://doi.org/10.1038/leu.2009.241CrossRefPubMedGoogle Scholar
  129. Pineault N, Buske C, Feuring-Buske M, Abramovich C, Rosten P, Hogge DE, Aplan PD, Humphries RK (2003) Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1. Blood 101(11):4529–4538.  https://doi.org/10.1182/blood-2002-08-2484CrossRefPubMedGoogle Scholar
  130. Port SA, Monecke T, Dickmanns A, Spillner C, Hofele R, Urlaub H, Ficner R, Kehlenbach RH (2015) Structural and functional characterization of CRM1-Nup214 interactions reveals multiple FG-binding sites involved in nuclear export. Cell Rep 13(4):690–702.  https://doi.org/10.1016/j.celrep.2015.09.042CrossRefPubMedGoogle Scholar
  131. Port SA, Mendes A, Valkova C, Spillner C, Fahrenkrog B, Kaether C, Kehlenbach RH (2016) The oncogenic fusion proteins SET-Nup214 and sequestosome-1 (SQSTM1)-Nup214 form dynamic nuclear bodies and differentially affect nuclear protein and poly(A)+ RNA export. J Biol Chem 291(44):23068–23083.  https://doi.org/10.1074/jbc.M116.735340CrossRefPubMedPubMedCentralGoogle Scholar
  132. Powers MA, Forbes DJ, Dahlberg JE, Lund E (1997) The vertebrate GLFG nucleoporin, Nup98, is an essential component of multiple RNA export pathways. J Cell Biol 136(2):241–250CrossRefPubMedPubMedCentralGoogle Scholar
  133. Pritchard CE, Fornerod M, Kasper LH, van Deursen JM (1999) 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 145(2):237–254CrossRefPubMedPubMedCentralGoogle Scholar
  134. Privette Vinnedge LM, Kappes F, Nassar N, Wells SI (2013) Stacking the DEK: from chromatin topology to cancer stem cells. Cell Cycle 12(1):51–66.  https://doi.org/10.4161/cc.23121CrossRefPubMedPubMedCentralGoogle Scholar
  135. Qin H, Malek S, Cowell JK, Ren M (2016) Transformation of human CD34+ hematopoietic progenitor cells with DEK-NUP214 induces AML in an immunocompromised mouse model. Oncogene 35(43):5686–5691.  https://doi.org/10.1038/onc.2016.118CrossRefPubMedPubMedCentralGoogle Scholar
  136. Quintas-Cardama A, Tong W, Manshouri T, Vega F, Lennon PA, Cools J, Gilliland DG, Lee F, Cortes J, Kantarjian H, Garcia-Manero G (2008) Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies. Leukemia 22(6):1117–1124.  https://doi.org/10.1038/leu.2008.80CrossRefPubMedGoogle Scholar
  137. Radu A, Moore MS, Blobel G (1995) The peptide repeat domain of nucleoporin Nup98 functions as a docking site in transport across the nuclear pore complex. Cell 81(2):215–222.  https://doi.org/10.1016/0092-8674(95)90331-3CrossRefPubMedPubMedCentralGoogle Scholar
  138. Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, Shows TB, Aplan PD (1998) NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia. Cancer Res 58(19):4269–4273PubMedGoogle Scholar
  139. Reader JC, Meekins JS, Gojo I, Ning Y (2007) A novel NUP98-PHF23 fusion resulting from a cryptic translocation t(11;17)(p15;p13) in acute myeloid leukemia. Leukemia 21(4):842–844.  https://doi.org/10.1038/sj.leu.2404579CrossRefPubMedGoogle Scholar
  140. Ricke RM, van Ree JH, van Deursen JM (2008) Whole chromosome instability and cancer: a complex relationship. Trends Genet 24(9):457–466.  https://doi.org/10.1016/j.tig.2008.07.002CrossRefPubMedPubMedCentralGoogle Scholar
  141. Roloff S, Spillner C, Kehlenbach RH (2013) Several phenylalanine-glycine motives in the nucleoporin Nup214 are essential for binding of the nuclear export receptor CRM1. J Biol Chem 288(6):3952–3963.  https://doi.org/10.1074/jbc.M112.433243CrossRefPubMedGoogle Scholar
  142. Romana S, Radford-Weiss I, Lapierre JM, Doye V, Geoffroy MC (2016) Formation of Nup98-containing nuclear bodies in HeLa sublines is linked to genomic rearrangements affecting chromosome 11. Chromosoma 125(4):789–805.  https://doi.org/10.1007/s00412-015-0567-0CrossRefPubMedGoogle Scholar
  143. Rosati R, La Starza R, Veronese A, Aventin A, Schwienbacher C, Vallespi T, Negrini M, Martelli MF, Mecucci C (2002) NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Blood 99(10):3857–3860CrossRefPubMedGoogle Scholar
  144. Rout MP, Aitchison JD, Magnasco MO, Chait BT (2003) Virtual gating and nuclear transport: the hole picture. Trends Cell Biol 13(12):622–628CrossRefPubMedGoogle Scholar
  145. Saito S, Miyaji-Yamaguchi M, Nagata K (2004) Aberrant intracellular localization of SET-CAN fusion protein, associated with a leukemia, disorganizes nuclear export. Int J Cancer 111(4):501–507CrossRefPubMedGoogle Scholar
  146. Saito S, Nouno K, Shimizu R, Yamamoto M, Nagata K (2008) Impairment of erythroid and megakaryocytic differentiation by a leukemia-associated and t(9;9)-derived fusion gene product, SET/TAF-Iβ-CAN/Nup214. J Cell Physiol 214(2):322–333.  https://doi.org/10.1002/jcp.21199CrossRefPubMedGoogle Scholar
  147. Saito S, Cigdem S, Okuwaki M, Nagata K (2016) Leukemia-associated Nup214 fusion proteins disturb the XPO1-mediated nuclear-cytoplasmic transport pathway and thereby the NF-κB signaling pathway. Mol Cell Biol 36(13):1820–1835.  https://doi.org/10.1128/MCB.00158-16CrossRefPubMedPubMedCentralGoogle Scholar
  148. Salsi V, Ferrari S, Gorello P, Fantini S, Chiavolelli F, Mecucci C, Zappavigna V (2014) NUP98 fusion oncoproteins promote aneuploidy by attenuating the mitotic spindle checkpoint. Cancer Res 74(4):1079–1090.  https://doi.org/10.1158/0008-5472.CAN-13-0912CrossRefPubMedGoogle Scholar
  149. Salsi V, Fantini S, Zappavigna V (2016) NUP98 fusion oncoproteins interact with the APC/C(Cdc20) as a pseudosubstrate and prevent mitotic checkpoint complex binding. Cell Cycle 15(17):2275–2287.  https://doi.org/10.1080/15384101.2016.1172156CrossRefPubMedPubMedCentralGoogle Scholar
  150. Salzman J, Gawad C, Wang PL, Lacayo N, Brown PO (2012) Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One 7(2):e30733.  https://doi.org/10.1371/journal.pone.0030733CrossRefPubMedPubMedCentralGoogle Scholar
  151. Sandahl JD, Coenen EA, Forestier E, Harbott J, Johansson B, Kerndrup G, Adachi S, Auvrignon A, Beverloo HB, Cayuela JM, Chilton L, Fornerod M, de Haas V, Harrison CJ, Inaba H, Kaspers GJ, Liang DC, Locatelli F, Masetti R, Perot C, Raimondi SC, Reinhardt K, Tomizawa D, von Neuhoff N, Zecca M, Zwaan CM, van den Heuvel-Eibrink MM, Hasle H (2014) t(6; 9)(p22; q34)/DEK-NUP214 rearranged pediatric myeloid leukemia: an international study of 62 patients. Haematologica 99(5):865–872.  https://doi.org/10.3324/haematol.2013.098517CrossRefPubMedPubMedCentralGoogle Scholar
  152. Sanden C, Ageberg M, Petersson J, Lennartsson A, Gullberg U (2013) Forced expression of the DEK-NUP214 fusion protein promotes proliferation dependent on upregulation of mTOR. BMC Cancer 13:440.  https://doi.org/10.1186/1471-2407-13-440CrossRefPubMedPubMedCentralGoogle Scholar
  153. Schindewolf C, Braun S, Domdey H (1996) In vitro generation of a circular exon from a linear pre-mRNA transcript. Nucleic Acids Res 24(7):1260–1266.  https://doi.org/10.1093/nar/24.7.1260CrossRefPubMedPubMedCentralGoogle Scholar
  154. Schmitt I, Gerace L (2001) In vitro analysis of nuclear transport mediated by the C-terminal shuttle domain of Tap. J Biol Chem 276(45):42355–42363.  https://doi.org/10.1074/jbc.M103916200CrossRefPubMedGoogle Scholar
  155. Schmitt C, von Kobbe C, Bachi A, Pante N, Rodrigues JP, Boscheron C, Rigaut G, Wilm M, Seraphin B, Carmo-Fonseca M, Izaurralde E (1999) Dbp5, a DEAD-box protein required for mRNA export, is recruited to the cytoplasmic fibrils of nuclear pore complex via a conserved interaction with CAN/Nup159p. EMBO J 18(15):4332–4347.  https://doi.org/10.1093/emboj/18.15.4332CrossRefPubMedPubMedCentralGoogle Scholar
  156. Schwartz TU (2005) Modularity within the architecture of the nuclear pore complex. Curr Opin Struct Biol 15(2):221–226CrossRefPubMedGoogle Scholar
  157. Seo SB, McNamara P, Heo S, Turner A, Lane WS, Chakravarti D (2001) Regulation of histone acetylation and transcription by INHAT, a human cellular complex containing the set oncoprotein. Cell 104(1):119–130CrossRefPubMedGoogle Scholar
  158. Shiba N, Ohki K, Kobayashi T, Hara Y, Yamato G, Tanoshima R, Ichikawa H, Tomizawa D, Park MJ, Shimada A, Sotomatsu M, Arakawa H, Horibe K, Adachi S, Taga T, Tawa A, Hayashi Y (2016) High PRDM16 expression identifies a prognostic subgroup of pediatric acute myeloid leukaemia correlated to FLT3-ITD, KMT2A-PTD, and NUP98-NSD1: the results of the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 trial. Br J Haematol 172(4):581–591.  https://doi.org/10.1111/bjh.13869CrossRefPubMedGoogle Scholar
  159. Slape C, Chung YJ, Soloway PD, Tessarollo L, Aplan PD (2007) Mouse embryonic stem cells that express a NUP98-HOXD13 fusion protein are impaired in their ability to differentiate and can be complemented by BCR-ABL. Leukemia 21(6):1239–1248CrossRefPubMedPubMedCentralGoogle Scholar
  160. Slovak ML, Gundacker H, Bloomfield CD, Dewald G, Appelbaum FR, Larson RA, Tallman MS, Bennett JM, Stirewalt DL, Meshinchi S, Willman CL, Ravindranath Y, Alonzo TA, Carroll AJ, Raimondi SC, Heerema NA (2006) A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare ‘poor prognosis’ myeloid malignancies. Leukemia 20(7):1295–1297.  https://doi.org/10.1038/sj.leu.2404233CrossRefPubMedGoogle Scholar
  161. Starke S, Jost I, Rossbach O, Schneider T, Schreiner S, Hung L-H, Bindereif A (2015) Exon circularization requires canonical splice signals. Cell Rep 10(1):103–111.  https://doi.org/10.1016/j.celrep.2014.12.002CrossRefPubMedGoogle Scholar
  162. Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA (2004) JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 18(2):189–218.  https://doi.org/10.1038/sj.leu.2403241CrossRefPubMedGoogle Scholar
  163. Struski S, Lagarde S, Bories P, Puiseux C, Prade N, Cuccuini W, Pages MP, Bidet A, Gervais C, Lafage-Pochitaloff M, Roche-Lestienne C, Barin C, Penther D, Nadal N, Radford-Weiss I, Collonge-Rame MA, Gaillard B, Mugneret F, Lefebvre C, Bart-Delabesse E, Petit A, Leverger G, Broccardo C, Luquet I, Pasquet M, Delabesse E (2017) NUP98 is rearranged in 3.8% of pediatric AML forming a clinical and molecular homogenous group with a poor prognosis. Leukemia 31(3):565–572.  https://doi.org/10.1038/leu.2016.267CrossRefPubMedGoogle Scholar
  164. Such E, Cervera J, Valencia A, Barragan E, Ibanez M, Luna I, Fuster O, Perez-Sirvent ML, Senent L, Sempere A, Martinez J, Martin-Aragones G, Sanz MA (2011) A novel NUP98/RARG gene fusion in acute myeloid leukemia resembling acute promyelocytic leukemia. Blood 117(1):242–245.  https://doi.org/10.1182/blood-2010-06-291658CrossRefPubMedGoogle Scholar
  165. Takeda A, Yaseen NR (2014) Nucleoporins and nucleocytoplasmic transport in hematologic malignancies. Semin Cancer Biol 27:3–10.  https://doi.org/10.1016/j.semcancer.2014.02.009CrossRefPubMedGoogle Scholar
  166. Takeda A, Sarma NJ, Abdul-Nabi AM, Yaseen NR (2010) Inhibition of CRM1-mediated nuclear export of transcription factors by leukemogenic NUP98 fusion proteins. J Biol Chem 285(21):16248–16257.  https://doi.org/10.1074/jbc.M109.048785CrossRefPubMedPubMedCentralGoogle Scholar
  167. Taketani T, Taki T, Ono R, Kobayashi Y, Ida K, Hayashi Y (2002a) 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 Chromosom Cancer 34(4):437–443.  https://doi.org/10.1002/gcc.10077CrossRefPubMedGoogle Scholar
  168. Taketani T, Taki T, Shibuya N, Ito E, Kitazawa J, Terui K, Hayashi Y (2002b) The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15). Cancer Res 62(1):33–37PubMedGoogle Scholar
  169. Taketani T, Taki T, Shibuya N, Kikuchi A, Hanada R, Hayashi Y (2002c) 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 62(16):4571–4574PubMedGoogle Scholar
  170. Taketani T, Taki T, Nakamura T, Kobayashi Y, Ito E, Fukuda S, Yamaguchi S, Hayashi Y (2010) High frequencies of simultaneous FLT3-ITD, WT1 and KIT mutations in hematological malignancies with NUP98-fusion genes. Leukemia 24(11):1975–1977.  https://doi.org/10.1038/leu.2010.207CrossRefPubMedGoogle Scholar
  171. Terry LJ, Wente SR (2009) Flexible gates: dynamic topologies and functions for FG nucleoporins in nucleocytoplasmic transport. Eukaryot Cell 8(12):1814–1827.  https://doi.org/10.1128/EC.00225-09CrossRefPubMedPubMedCentralGoogle Scholar
  172. Thakar K, Karaca S, Port SA, Urlaub H, Kehlenbach RH (2013) Identification of CRM1-dependent nuclear export cargos using quantitative mass spectrometry. Mol Cell Proteomics 12(3):664–678.  https://doi.org/10.1074/mcp.M112.024877CrossRefPubMedGoogle Scholar
  173. Thanasopoulou A, Tzankov A, Schwaller J (2014) Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction. Haematologica 99(9):1465–1471.  https://doi.org/10.3324/haematol.2013.100917CrossRefPubMedPubMedCentralGoogle Scholar
  174. Timney BL, Raveh B (2016) Simple rules for passive diffusion through the nuclear pore complex. J Cell Biol 215(1):57–76CrossRefPubMedPubMedCentralGoogle Scholar
  175. Tosi S, Ballabio E, Teigler-Schlegel A, Boultwood J, Bruch J, Harbott J (2005) 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 Chromosom Cancer 44(3):225–232.  https://doi.org/10.1002/gcc.20233CrossRefPubMedGoogle Scholar
  176. Valkov E, Dean JC, Jani D, Kuhlmann SI, Stewart M (2012) Structural basis for the assembly and disassembly of mRNA nuclear export complexes. Biochim Biophys Acta 1819(6):578–592.  https://doi.org/10.1016/j.bbagrm.2012.02.017CrossRefPubMedGoogle Scholar
  177. van Deursen J, Boer J, Kasper L, Grosveld G (1996) G2 arrest and impaired nucleocytoplasmic transport in mouse embryos lacking the proto-oncogene CAN/Nup214. EMBO J 15(20):5574–5583PubMedPubMedCentralCrossRefGoogle Scholar
  178. Van Vlierberghe P, van Grotel M, Tchinda J, Lee C, Beverloo HB, van der Spek PJ, Stubbs A, Cools J, Nagata K, Fornerod M, Buijs-Gladdines J, Horstmann M, van Wering ER, Soulier J, Pieters R, Meijerink JP (2008) The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. Blood 111(9):4668–4680.  https://doi.org/10.1182/blood-2007-09-111872CrossRefPubMedPubMedCentralGoogle Scholar
  179. van Zutven LJCM, Önen E, Velthuizen SCJM, van Drunen E, von Bergh ARM, van den Heuvel-Eibrink MM, Veronese A, Mecucci C, Negrini M, de Greef GE, Beverloo HB (2006) Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene. Genes Chromosom Cancer 45 (5):437–446. doi: https://doi.org/10.1002/gcc.20308CrossRefPubMedGoogle Scholar
  180. von Lindern M, Breems D, van Baal S, Adriaansen H, Grosveld G (1992a) Characterization of the translocation breakpoint sequences of two DEK-CAN fusion genes present in t(6;9) acute myeloid leukemia and a SET-CAN fusion gene found in a case of acute undifferentiated leukemia. Genes Chromosom Cancer 5(3):227–234CrossRefGoogle Scholar
  181. von Lindern M, Fornerod M, van Baal S, Jaegle M, de Wit T, Buijs A, Grosveld G (1992b) 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 12(4):1687–1697CrossRefGoogle Scholar
  182. von Lindern M, van Baal S, Wiegant J, Raap A, Hagemeijer A, Grosveld G (1992c) Can, a putative oncogene associated with myeloid leukemogenesis, may be activated by fusion of its 3′ half to different genes: characterization of the set gene. Mol Cell Biol 12(8):3346–3355CrossRefGoogle Scholar
  183. von Moeller H, Basquin C, Conti E (2009) The mRNA export protein DBP5 binds RNA and the cytoplasmic nucleoporin NUP214 in a mutually exclusive manner. Nat Struct Mol Biol 16(3):247–254.  https://doi.org/10.1038/nsmb.1561CrossRefGoogle Scholar
  184. Waldmann T, Scholten I, Kappes F, Hu HG, Knippers R (2004) The DEK protein—an abundant and ubiquitous constituent of mammalian chromatin. Gene 343(1):1–9.  https://doi.org/10.1016/j.gene.2004.08.029CrossRefPubMedGoogle Scholar
  185. Walther TC, Pickersgill HS, Cordes VC, Goldberg MW, Allen TD, Mattaj IW, Fornerod M (2002) The cytoplasmic filaments of the nuclear pore complex are dispensable for selective nuclear protein import. J Cell Biol 158(1):63–77CrossRefPubMedPubMedCentralGoogle Scholar
  186. Wang X, Babu JR, Harden JM, Jablonski SA, Gazi MH, Lingle WL, de Groen PC, Yen TJ, van Deursen JM (2001) The mitotic checkpoint protein hBUB3 and the mRNA export factor hRAE1 interact with GLE2p-binding sequence (GLEBS)-containing proteins. J Biol Chem 276(28):26559–26567.  https://doi.org/10.1074/jbc.M101083200CrossRefPubMedGoogle Scholar
  187. Wang GG, Cai L, Pasillas MP, Kamps MP (2007) NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol 9(7):804–812. http://www.nature.com/ncb/journal/v9/n7/suppinfo/ncb1608_S1.htmlCrossRefPubMedGoogle Scholar
  188. Wang GG, Song J, Wang Z, Dormann HL, Casadio F, Li H, Luo J-L, Patel DJ, Allis CD (2009) Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature 459(7248):847–851. http://www.nature.com/nature/journal/v459/n7248/suppinfo/nature08036_S1.htmlCrossRefPubMedPubMedCentralGoogle Scholar
  189. Xu S, Powers MA (2010) Nup98-homeodomain fusions interact with endogenous Nup98 during interphase and localize to kinetochores and chromosome arms during mitosis. Mol Biol Cell 21(9):1585–1596.  https://doi.org/10.1091/mbc.E09-07-0561CrossRefPubMedPubMedCentralGoogle Scholar
  190. Yamamoto K, Nakamachi Y, Yakushijin K, Funakoshi Y, Okamura A, Kawano S, Matsuoka H, Minami H (2012) Expression of the novel NUP98/PSIP1 fusion transcripts in myelodysplastic syndrome with t(9;11)(p22;p15). Eur J Haematol 88(3):244–248.  https://doi.org/10.1111/j.1600-0609.2011.01736.xCrossRefPubMedGoogle Scholar
  191. Yassin ER, Sarma NJ, Abdul-Nabi AM, Dombrowski J, Han Y, Takeda A, Yaseen NR (2009) Dissection of the transformation of primary human hematopoietic cells by the oncogene NUP98-HOXA9. PLoS One 4(8):e6719.  https://doi.org/10.1371/journal.pone.0006719CrossRefPubMedPubMedCentralGoogle Scholar
  192. Zhang X, Yamada M, Mabuchi N, Shida H (2003) Cellular requirements for CRM1 import and export. J Biochem 134(5):759–764CrossRefPubMedGoogle Scholar
  193. Zhao CL, Mahboobi SH, Moussavi-Baygi R, Mofrad MR (2014) The interaction of CRM1 and the nuclear pore protein Tpr. PLoS One 9(4):e93709.  https://doi.org/10.1371/journal.pone.0093709CrossRefPubMedPubMedCentralGoogle Scholar
  194. Zhou MH, Yang QM (2014) NUP214 fusion genes in acute leukemia (Review). Oncol Lett 8(3):959–962.  https://doi.org/10.3892/ol.2014.2263CrossRefPubMedPubMedCentralGoogle Scholar
  195. Zhu HH, Zhao XS, Qin YZ, Lai YY, Jiang H (2016) B-cell acute lymphoblastic leukemia associated with SET-NUP214 rearrangement: a case report and review of the literature. Oncol Lett 11(4):2644–2650.  https://doi.org/10.3892/ol.2016.4260CrossRefPubMedPubMedCentralGoogle Scholar
  196. Zolotukhin AS, Felber BK (1999) Nucleoporins nup98 and nup214 participate in nuclear export of human immunodeficiency virus type 1 Rev. J Virol 73(1):120–127PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Nuno Martins
    • 1
  • Adélia Mendes
    • 1
  • Birthe Fahrenkrog
    • 1
  1. 1.Institute for Molecular Biology and Medicine, Universite Libre de BruxellesCharleroiBelgium

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