Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

The ets transcription factor Fli-1 in development, cancer and disease

Oncogene volume 34, pages 2022–2031 (2015)Cite this article

Subjects

Abstract

Friend leukemia virus-induced erythroleukemia-1 (Fli-1), an E26 transformation specific (ETS) transcription factor, was isolated a quarter century ago through a retrovirus mutagenesis screen. Fli-1 has since been recognized to play critical roles in normal development and homeostasis. For example, it transcriptionally regulates genes that drive normal hematopoiesis and vasculogenesis. Indeed, Fli-1 is one of 10 key regulators of hematopoietic stem/progenitor cell maintenance and differentiation. Aberrant expression of Fli-1 also underlies a number of virally induced leukemias, including Friend virus-induced erythroleukemia and various types of human cancers, and it is the target of chromosomal translocations in childhood Ewing's sarcoma. Abnormal expression of Fli-1 is important in the etiology of autoimmune diseases such as systemic lupus erythematosus and systemic sclerosis. These studies establish Fli-1 as a strong candidate for drug development. Despite difficulties in targeting transcription factors, recent studies identified small-molecule inhibitors for Fli-1. Here we review past and ongoing research on Fli-1 with emphasis on its mechanistic function in autoimmune disease and malignant transformation. The significance of identifying Fli-1 inhibitors and their clinical applications for treatment of disease and cancer with deregulated Fli-1 expression are discussed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Ben-David Y, Giddens EB, Bernstein A . Identification and mapping of a common proviral integration site Fli-1 in erythroleukemia cells induced by Friend murine leukemia virus. Proc Natl Acad Sci USA 1990; 87: 1332–1336.

    CAS  Google Scholar 

  2. Ben-David Y, Giddens EB, Letwin K, Bernstein A . Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1. Genes Dev 1991; 5: 908–918.

    CAS  Google Scholar 

  3. Bergeron D, Poliquin L, Houde J, Barbeau B, Rassart E . Analysis of proviruses integrated in Fli-1 and Evi-1 regions in Cas-Br-E MuLV-induced non-T-, non-B-cell leukemias. Virology 1992; 191: 661–669.

    CAS  Google Scholar 

  4. Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 1992; 359: 162–165.

    CAS  Google Scholar 

  5. Ordóñez JL, Osuna D, Herrero D, de Alava E, Madoz-Gúrpide J, Ordóñez JL et al. Advances in Ewing's sarcoma research: where are we now and what lies ahead? Cancer Res 2009; 69: 7140–7150.

    Google Scholar 

  6. Leavey PJ, Collier AB . Ewing sarcoma: prognostic criteria, outcomes and future treatment. Expert Rev Anticancer Ther 2008; 8: 617–624.

    CAS  Google Scholar 

  7. Riggi N, Stamenkovic I . The Biology of Ewing sarcoma. Cancer Lett 2007; 254: 1–10.

    CAS  Google Scholar 

  8. Owen LA, Lessnick SL . Identification of target genes in their native cellular context: an analysis of EWS/FLI in Ewing's sarcoma. Cell Cycle 2006; 5: 2049–2053.

    CAS  Google Scholar 

  9. Laudet V, Hänni C, Stéhelin D, Duterque-Coquillaud M . Molecular phylogeny of the ETS gene family. Oncogene 1999; 18: 1351–1359.

    CAS  Google Scholar 

  10. Schütte J, Moignard V, Göttgens B . Establishing the stem cell state: insights from regulatory network analysis of blood stem cell development. Wiley Interdiscip Rev Syst Biol Med 2012; 4: 285–295.

    Google Scholar 

  11. Wilson NK, Foster SD, Wang X, Knezevic K, Schütte J, Kaimakis P et al. Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators. Cell Stem Cell 2010; 7: 532–544.

    CAS  Google Scholar 

  12. Wei GH, Badis G, Berger MF, Kivioja T, Palin K, Enge M et al. Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo. EMBO J 2010; 29: 2147–2160.

    CAS  Google Scholar 

  13. Camões MJ, Paulo P, Ribeiro FR, Barros-Silva JD, Almeida M, Costa VL et al. Potential downstream target genes of aberrant ETS transcription factors are differentially affected in Ewing's sarcoma and prostate carcinoma. PLoS ONE 2012; 7: e49819.

    Google Scholar 

  14. Starck J, Weiss-Gayet M, Gonnet C, Guyot B, Vicat JM, Morlé F . Inducible Fli-1 gene deletion in adult mice modifies several myeloid lineage commitment decisions and accelerates proliferation arrest and terminal erythrocytic differentiation. Blood 2010; 116: 4795–4805.

    CAS  Google Scholar 

  15. Carmichael CL, Metcalf D, Henley KJ, Kruse EA, Di Rago L, Mifsud S et al. Hematopoietic overexpression of the transcription factor Erg induces lymphoid and erythro-megakaryocytic leukemia. Proc Natl Acad Sci USA 2012; 109: 15437–15442.

    CAS  Google Scholar 

  16. Kruse EA, Loughran SJ, Baldwin TM, Josefsson EC, Ellis S, Watson DK et al. Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage. Proc Natl Acad Sci USA 2009; 106: 13814–13819.

    CAS  Google Scholar 

  17. Pusztaszeri MP, Seelentag W, Bosman FT . Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues. J Histochem Cytochem 2006; 54: 385–395.

    CAS  Google Scholar 

  18. Hewett PW, Nishi K, Daft EL, Clifford MJ . Selective expression of erg isoforms in human endothelial cells. Int J Biochem Cell Biol 2001; 33: 347–355.

    CAS  Google Scholar 

  19. Mélet F, Motro B, Rossi DJ, Zhang L, Bernstein A . Generation of a novel Fli-1 protein by gene targeting leads to a defect in thymus development and a delay in Friend virus-induced erythroleukemia. Mol Cell Biol 1996; 16: 2708–2718.

    Google Scholar 

  20. Tamir A, Howard J, Higgins RR, Li YJ, Berger L, Zacksenhaus E et al. Fli-1, an Ets-related transcription factor, regulates erythropoietin-induced erythroid proliferation and differentiation: evidence for direct transcriptional repression of the Rb gene during differentiation. Mol Cell Biol 1999; 19: 4452–4464.

    CAS  Google Scholar 

  21. Zochodne B, Truong AH, Stetler K, Higgins RR, Howard J, Dumont D et al. Epo regulates erythroid proliferation and differentiation through distinct signaling pathways: implication for erythropoiesis and Friend virus-induced erythroleukemia. Oncogene 2000; 19: 2296–2304.

    CAS  Google Scholar 

  22. Masuya M, Moussa O, Abe T, Deguchi T, Higuchi T, Ebihara Y et al. Dysregulation of granulocyte, erythrocyte, and NK cell lineages in Fli-1 gene-targeted mice. Blood 2005; 105: 95–102.

    CAS  Google Scholar 

  23. Spyropoulos DD, Pharr PN, Lavenburg KR, Jackers P, Papas TS, Ogawa M et al. Hemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor. Mol Cell Biol 2000; 20: 5643–5652.

    CAS  Google Scholar 

  24. Anderson MK, Hernandez-Hoyos G, Diamond RA, Rothenberg EV . Precise developmental regulation of Ets family transcription factors during specification and commitment to the T cell lineage. Development 1999; 126: 3131–3148.

    CAS  Google Scholar 

  25. Svenson JL, Chike-Harris K, Amria MY, Nowling TK . The mouse and human Fli1 genes are similarly regulated by Ets factors in T cells. Genes Immun 2010; 11: 161–172.

    CAS  Google Scholar 

  26. Hart A, Melet F, Grossfeld P, Chien K, Jones C, Tunnacliffe A et al. Fli-1 is required for murine vascular and megakaryocytic development and is hemizygously deleted in patients with thrombocytopenia. Immunity 2000; 13: 167–177.

    CAS  Google Scholar 

  27. Smeets MF, Chan AC, Dagger S, Bradley CK, Wei A, Izon DJ . Fli-1 overexpression in hematopoietic progenitors deregulates T cell development and induces pre-T cell lymphoblastic leukaemia/lymphoma. PLoS ONE 2013; 8: e62346.

    CAS  Google Scholar 

  28. Zhang L, Eddy A, Teng YT, Fritzler M, Kluppel M, Melet F et al. An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes. Mol Cell Biol 1995; 15: 6961–6970.

    CAS  Google Scholar 

  29. Moussa O, LaRue AC, Abangan RS Jr., Williams CR, Zhang XK, Masuya M et al. Thrombocytopenia in mice lacking the carboxy-terminal regulatory domain of the Ets transcription factor Fli1. Mol Cell Biol 2010; 30: 5194–5206.

    CAS  Google Scholar 

  30. Zhang XK, Moussa O, LaRue A, Bradshaw S, Molano I, Spyropoulos DD et al. The transcription factor Fli-1 modulates marginal zone and follicular B cell development in mice. J Immunol 2008; 181: 1644–1654.

    CAS  Google Scholar 

  31. Bradshaw S, Zheng WJ, Tsoi LC, Gilkeson G, Zhang XK . A role for Fli-1 in B cell proliferation: implications for SLE pathogenesis. Clin Immunol 2008; 129: 19–30.

    CAS  Google Scholar 

  32. Okada Y, Nobori H, Shimizu M, Watanabe M, Yonekura M, Nakai T et al. Multiple ETS family proteins regulate PF4 gene expression by binding to the same ETS binding site. PLoS ONE 2011; 6: e24837.

    CAS  Google Scholar 

  33. Krishnamurti L, Neglia JP, Nagarajan R, Berry SA, Lohr J, Hirsch B et al. Paris-Trousseau syndrome platelets in a child with Jacobsen's syndrome. Am J Hematol 2001; 66: 295–299.

    CAS  Google Scholar 

  34. Favier R, Jondeau K, Boutard P, Grossfeld P, Reinert P, Jones C et al. Paris-Trousseau syndrome: clinical, hematological, molecular data of ten new cases. Thromb Haemost 2003; 90: 893–897.

    CAS  Google Scholar 

  35. Wenger SL, Grossfeld PD, Siu BL, Coad JE, Keller FG, Hummel M . Molecular characterization of an 11q interstitial deletion in a patient with the clinical features of Jacobsen syndrome. Am J Med Genet A 2006; 140: 704–708.

    Google Scholar 

  36. Gosiengfiao Y, Horvat R, Thompson A . Transcription factors GATA-1 and Fli-1 regulate human HOXA10 expression in megakaryocytic cells. DNA Cell Biol 2007; 26: 577–587.

    CAS  Google Scholar 

  37. Stockley J, Morgan NV, Bem D, Lowe GC, Lordkipanidzé M, Dawood B et al. Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects. Blood 2013; 122: 4090–4093.

    CAS  Google Scholar 

  38. Suzuki E, Williams S, Sato S, Gilkeson G, Watson DK, Zhang XK . The transcription factor Fli-1 regulates monocyte, macrophage and dendritic cell development in mice. Immunology 2013; 139: 318–327.

    CAS  Google Scholar 

  39. Remy P, Sénan F, Meyer D, Mager AM, Hindelang C . Overexpression of the Xenopus Xl-fli gene during early embryogenesis leads to anomalies in head and heart development and erythroid differentiation. Int J Dev Biol 1996; 40: 577–589.

    CAS  Google Scholar 

  40. Meyer D, Wolff CM, Stiegler P, Sénan F, Befort N, Befort JJ et al. Xl-fli, the Xenopus homologue of the fli-1 gene, is expressed during embryogenesis in a restricted pattern evocative of neural crest cell distribution. Mech Dev 1993; 44: 109–121.

    CAS  Google Scholar 

  41. Brown LA, Rodaway AR, Schilling TF, Jowett T, Ingham PW, Patient RK et al. Insights into early vasculogenesis revealed by expression of the ETS-domain transcription factor Fli-1 in wild-type and mutant zebrafish embryos. Mech Dev 2000; 90: 237–252.

    CAS  Google Scholar 

  42. Lawson ND, Weinstein BM . In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev Biol 2002; 248: 307–318.

    CAS  Google Scholar 

  43. Pham VN, Lawson ND, Mugford JW, Dye L, Castranova D, Lo B et al. Combinatorial function of ETS transcription factors in the developing vasculature. Dev Biol 2007; 303: 772–783.

    CAS  Google Scholar 

  44. Liu F, Patient R . Genome-wide analysis of the zebrafish ETS family identifies three genes required for hemangioblast differentiation or angiogenesis. Circ Res 2008; 103: 1147–1154.

    CAS  Google Scholar 

  45. Liu F, Walmsley M, Rodaway A, Patient R . Fli1 acts at the top of the transcriptional network driving blood and endothelial development. Curr Biol 2008; 18: 1234–1240.

    CAS  Google Scholar 

  46. Li L, Chen D, Li J, Wang X, Wang N, Xu C et al. Aggf1 acts at the top of the genetic regulatory hierarchy in specification of hemangioblasts in zebrafish. Blood 2013; 123: 501–508.

    Google Scholar 

  47. Pimanda JE, Chan WY, Donaldson IJ, Bowen M, Green AR, Göttgens B . Endoglin expression in the endothelium is regulated by Fli-1, Erg, and Elf-1 acting on the promoter and a −8-kb enhancer. Blood 2006; 107: 4737–4745.

    CAS  Google Scholar 

  48. Landry JR, Kinston S, Knezevic K, Donaldson IJ, Green AR, Göttgens B . Fli1, Elf1, and Ets1 regulate the proximal promoter of the LMO2 gene in endothelial cells. Blood 2005; 106: 2680–2687.

    CAS  Google Scholar 

  49. Göttgens B, Broccardo C, Sanchez MJ, Deveaux S, Murphy G, Göthert JR et al. The scl +18/19 stem cell enhancer is not required for hematopoiesis: identification of a 5' bifunctional hematopoietic-endothelial enhancer bound by Fli-1 and Elf-1. Mol Cell Biol 2004; 24: 1870–1883.

    Google Scholar 

  50. Göttgens B, Nastos A, Kinston S, Piltz S, Delabesse EC, Stanley M et al. Establishing the transcriptional programme for blood: the SCL stem cell enhancer is regulated by a multiprotein complex containing Ets and GATA factors. EMBO J 2002; 21: 3039–3050.

    Google Scholar 

  51. Heo SH, Choi YJ, Ryoo HM, Cho JY . Expression profiling of ETS and MMP factors in VEGF-activated endothelial cells: role of MMP-10 in VEGF-induced angiogenesis. J Cell Physiol 2010; 224: 734–742.

    CAS  Google Scholar 

  52. De Val S, Black BL . Transcriptional control of endothelial cell development. Dev Cell 2009; 16: 180–195.

    CAS  Google Scholar 

  53. McLaughlin F, Ludbrook VJ, Cox J, von Carlowitz I, Brown S, Randi AM . Combined genomic and antisense analysis reveals that the transcription factor Erg is implicated in endothelial cell differentiation. Blood 2001; 98: 3332–3339.

    CAS  Google Scholar 

  54. Ginsberg M, James D, Ding BS, Nolan D, Geng F, Butler JM et al. Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression. Cell 2012; 151: 559–575.

    CAS  Google Scholar 

  55. Le Bras A, Samson C, Trentini M, Caetano B, Lelievre E, Mattot V et al. VE-statin/egfl7 expression in endothelial cells is regulated by a distal enhancer and a proximal promoter under the direct control of Erg and GATA-2. PLoS ONE 2010; 5: e12156.

    Google Scholar 

  56. Soncin F, Mattot V, Lionneton F, Spruyt N, Lepretre F, Begue A et al. VE-statin, an endothelial repressor of smooth muscle cell migration. EMBO J 2003; 22: 5700–5711.

    CAS  Google Scholar 

  57. Lelièvre E, Lionneton F, Mattot V, Spruyt N, Soncin F . Ets-1 regulates fli-1 expression in endothelial cells. Identification of ETS binding sites in the fli-1 gene promoter. J Biol Chem 2002; 277: 25143–25151.

    Google Scholar 

  58. Georgiou P, Maroulakou I, Green J, Dantis P, Romanospica V, Kottaridis S et al. Expression of ets family of genes in systemic lupus erythematosus and Sjogren's syndrome. Int J Oncol 1996; 9: 9–18.

    CAS  Google Scholar 

  59. Zhang XK, Gallant S, Molano I, Moussa OM, Ruiz P, Spyropoulos DD et al. Decreased expression of the Ets family transcription factor Fli-1 markedly prolongs survival and significantly reduces renal disease in MRL/lpr mice. J Immunol 2004; 173: 6481–6489.

    CAS  Google Scholar 

  60. Mathenia J, Reyes-Cortes E, Williams S, Molano I, Ruiz P, Watson DK et al. Impact of Fli-1 transcription factor on autoantibody and lupus nephritis in NZM2410 mice. Clin Exp Immunol 2010; 162: 362–371.

    CAS  Google Scholar 

  61. Suzuki E, Karam E, Williams S, Watson DK, Gilkeson G, Zhang XK . Fli-1 transcription factor affects glomerulonephritis development by regulating expression of monocyte chemoattractant protein-1 in endothelial cells in the kidney. Clin Immunol 2012; 145: 201–208.

    CAS  Google Scholar 

  62. Molano I, Mathenia J, Ruiz P, Gilkeson GS, Zhang XK . Decreased expression of Fli-1 in bone marrow-derived haematopoietic cells significantly affects disease development in Murphy Roths Large/lymphoproliferation (MRL/lpr) mice. Clin Exp Immunol 2010; 160: 275–282.

    CAS  Google Scholar 

  63. Nowling TK, Fulton JD, Chike-Harris K, Gilkeson GS . Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes. Mol Immunol 2008; 45: 1–12.

    CAS  Google Scholar 

  64. Morris EE, Amria MY, Kistner-Griffin E, Svenson JL, Kamen DL, Gilkeson GS et al. A GA microsatellite in the Fli1 promoter modulates gene expression and is associated with systemic lupus erythematosus patients without nephritis. Arthritis Res Ther 2010; 12: R212.

    Google Scholar 

  65. Sakthianandeswaren A, Curtis JM, Elso C, Kumar B, Baldwin TM, Lopaticki S et al. Fine mapping of Leishmania major susceptibility Locus lmr2 and evidence of a role for Fli1 in disease and wound healing. Infect Immun 2010; 78: 2734–2744.

    CAS  Google Scholar 

  66. Tani C, Bellando Randone S, Guiducci S, Della Rossa A . Systemic sclerosis: a critical digest of the recent literature. Clin Exp Rheumatol 2013; 31: 172–179.

    Google Scholar 

  67. Wang Y, Fan PS, Kahaleh B . Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum 2006; 54: 2271–2279.

    CAS  Google Scholar 

  68. Asano Y, Bujor AM, Trojanowska M . The impact of Fli1 deficiency on the pathogenesis of systemic sclerosis. J Dermatol Sci 2010; 59: 153–162.

    CAS  Google Scholar 

  69. Asano Y, Stawski L, Hant F, Highland K, Silver R, Szalai G et al. Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy. Am J Pathol 2010; 176: 1983–1998.

    CAS  Google Scholar 

  70. Bujor AM, Asano Y, Haines P, Lafyatis R, Trojanowska M . The c-Abl tyrosine kinase controls protein kinase Cδ-induced Fli-1 phosphorylation in human dermal fibroblasts. Arthritis Rheum 2011; 63: 1729–1737.

    CAS  Google Scholar 

  71. Asano Y, Trojanowska M . Phosphorylation of Fli1 at threonine 312 by protein kinase C delta promotes its interaction with p300/CREB-binding protein-associated factor and subsequent acetylation in response to transforming growth factor beta. Mol Cell Biol 2009; 29: 1882–1894.

    CAS  Google Scholar 

  72. Asano Y, Czuwara J, Trojanowska M . Transforming growth factor-beta regulates DNA binding activity of transcription factor Fli1 by p300/CREB-binding protein-associated factor-dependent acetylation. J Biol Chem 2007; 282: 34672–34683.

    CAS  Google Scholar 

  73. Noda S, Asano Y, Akamata K, Aozasa N, Taniguchi T, Takahashi T et al. Constitutive activation of c-Abl/protein kinase C-δ/Fli1 pathway in dermal fibroblasts derived from patients with localized scleroderma. Br J Dermatol 2012; 167: 1098–1105.

    CAS  Google Scholar 

  74. Elkareh J, Periyasamy SM, Shidyak A, Vetteth S, Schroeder J, Raju V et al. Marinobufagenin induces increases in procollagen expression in a process involving protein kinase C and Fli-1: implications for uremic cardiomyopathy. Am J Physiol Renal Physiol 2009; 296: F1219–F1226.

    CAS  Google Scholar 

  75. Haller ST, Kennedy DJ, Shidyak A, Budny GV, Malhotra D, Fedorova OV et al. Monoclonal antibody against marinobufagenin reverses cardiac fibrosis in rats with chronic renal failure. Am J Hypertens 2012; 25: 690–696.

    CAS  Google Scholar 

  76. Nikitina ER, Mikhailov AV, Nikandrova ES, Frolova EV, Fadeev AV, Shman VV et al. In preeclampsia endogenous cardiotonic steroids induce vascular fibrosis and impair relaxation of umbilical arteries. J Hypertens 2011; 29: 769–776.

    CAS  Google Scholar 

  77. Ott DE, Keller J, Rein A . 10A1 MuLV induces a murine leukemia that expresses hematopoietic stem cell markers by a mechanism that includes fli-1 integration. Virology 1994; 205: 563–568.

    CAS  Google Scholar 

  78. Prassad DD, Rao VN, Reddy ES . Structure and expression of human Fli-1 gene. Cancer Res 1992; 52: 5833–5837.

    Google Scholar 

  79. Watson DK, Smyth FE, Thompson DM, Cheng JQ, Testa JR, Papas TS et al. The ERGB/Fli-1 gene: isolation and characterization of a new member of the family of human ETS transcription factors. Cell Growth Differ 1992; 3: 705–713.

    CAS  Google Scholar 

  80. Ano S, Pereira R, Pironin M, Lesault I, Milley C, Lebigot I et al. Erythroblast transformation by FLI-1 depends upon its specific DNA binding and transcriptional activation properties. J Biol Chem 2004; 279: 2993–3002.

    CAS  Google Scholar 

  81. Athanasiou M, Mavrothalassitis G, Sun-Hoffman L, Blair DG . FLI-1 is a suppressor of erythroid differentiation in human hematopoietic cells. Leukemia 2000; 14: 439–445.

    CAS  Google Scholar 

  82. Pereira R, Quang CT, Lesault I, Dolznig H, Beug H, Ghysdael J . FLI-1 inhibits differentiation and induces proliferation of primary erythroblasts. Oncogene 1999; 18: 1597–1608.

    CAS  Google Scholar 

  83. Lee CR, Cervi D, Truong AH, Li YJ, Sarkar A, Ben-David Y . Friend virus-induced erythroleukemias: a unique and well-defined mouse model for the development of leukemia. Anticancer Res 2003; 23: 2159–2166.

    CAS  Google Scholar 

  84. Torchia EC, Boyd K, Rehg JE, Qu C, Baker SJ . EWS/FLI-1 induces rapid onset of myeloid/erythroid leukemia in mice. Mol Cell Biol 2007; 27: 7918–7934.

    CAS  Google Scholar 

  85. Lesault I, Quang CT, Frampton J, Ghysdael J . Direct regulation of BCL-2 by FLI-1 is involved in the survival of FLI-1-transformed erythroblasts. EMBO J 2002; 21: 694–703.

    CAS  Google Scholar 

  86. Truong AH, Cervi D, Lee J, Ben-David Y . Direct transcriptional regulation of MDM2 by Fli-1. Oncogene 2005; 24: 962–969.

    CAS  Google Scholar 

  87. Wong KS, Li YJ, Howard J, Ben-David Y . Loss of p53 in F-MuLV induced-erythroleukemias accelerates the acquisition of mutational events that confers immortality and growth factor independence. Oncogene 1999; 18: 5525–5534.

    CAS  Google Scholar 

  88. Li Y, Tanaka K, Fan X, Nakatani F, Li X, Nakamura T, Takasaki M et al. Inhibition of the transcriptional function of p53 by EWS-Fli1 chimeric protein in Ewing Family Tumors. Cancer Lett 2010; 294: 57–65.

    CAS  Google Scholar 

  89. Ban J, Bennani-Baiti IM, Kauer M, Schaefer KL, Poremba C, Jug G et al. EWS-FLI1 suppresses NOTCH-activated p53 in Ewing's sarcoma. Cancer Res 2008; 68: 7100–7109.

    CAS  Google Scholar 

  90. Lakhanpal GK, Vecchiarelli-Federico LM, Li YJ, Cui JW, Bailey ML, Spaner DE et al. The inositol phosphatase SHIP-1 is negatively regulated by Fli-1 and its loss accelerates leukemogenesis. Blood 2010; 116: 428–436.

    CAS  Google Scholar 

  91. Juban G, Giraud G, Guyot B, Belin S, Diaz JJ, Starck J et al. Spi-1 and Fli-1 directly activate common target genes involved in ribosome biogenesis in Friend erythroleukemic cells. Mol Cell Biol 2009; 29: 2852–2864.

    CAS  Google Scholar 

  92. Klemsz MJ, Maki RA, Papayannopoulou T, Moore J, Hromas R . Characterization of the ets oncogene family member, fli-1. J Biol Chem 1993; 268: 5769–5773.

    CAS  Google Scholar 

  93. Cui JW, Vecchiarelli-Federico LM, Li YJ, Wang GJ, Ben-David Y . Continuous Fli-1 expression plays an essential role in the proliferation and survival of F-MuLV-induced erythroleukemia and human erythroleukemia. Leukemia 2009; 23: 1311–1319.

    CAS  Google Scholar 

  94. Kornblau SM, Qiu YH, Zhang N, Singh N, Faderl S, Ferrajoli A et al. Abnormal expression of FLI1 protein is an adverse prognostic factor in acute myeloid leukemia. Blood 2011; 118: 5604–5612.

    CAS  Google Scholar 

  95. Tyybäkinoja A, Saarinen-Pihkala U, Elonen E, Knuutila S . Amplified, lost, and fused genes in 11q23-25 amplicon in acute myeloid leukemia, an array-CGH study. Genes Chromosomes Cancer 2006; 45: 257–264.

    Google Scholar 

  96. Kwiatkowski BA, Zielinska-Kwiatkowska AG, Bauer TR Jr., Hickstein DD . The ETS family member Tel antagonizes the Fli-1 phenotype in hematopoietic cells. Blood Cells Mol Dis 2000; 26: 84–90.

    CAS  Google Scholar 

  97. Kwiatkowski BA, Bastian LS, Bauer TR Jr., Tsai S, Zielinska-Kwiatkowska AG, Hickstein DD . The ets family member Tel binds to the Fli-1 oncoprotein and inhibits its transcriptional activity. J Biol Chem 1998; 273: 17525–17530.

    CAS  Google Scholar 

  98. Martens JH, Mandoli A, Simmer F, Wierenga BJ, Saeed S, Singh AA et al. ERG and FLI1 binding sites demarcate targets for aberrant epigenetic regulation by AML1-ETO in acute myeloid leukemia. Blood 2012; 120: 4038–4048.

    CAS  Google Scholar 

  99. Johnson AD, Pambuccian SE, Andrade RS, Dolan MM, Aslan DL . Ewing sarcoma and primitive neuroectodermal tumor of the esophagus: report of a case and review of literature. Int J Surg Pathol 2010; 18: 388–393.

    Google Scholar 

  100. Mhawech-Fauceglia P, Herrmann FR, Bshara W, Odunsi K, Terracciano L, Sauter G et al. Friend leukaemia integration-1 expression in malignant and benign tumours: a multiple tumour tissue microarray analysis using polyclonal antibody. J Clin Pathol 2007; 60: 694–700.

    CAS  Google Scholar 

  101. Sakurai T, Kondoh N, Arai M, Hamada J, Yamada T, Kihara-Negishi F et al. Functional roles of Fli-1, a member of the Ets family of transcription factors, in human breast malignancy. Cancer Sci 2007; 98: 1775–1784.

    CAS  Google Scholar 

  102. Torlakovic EE, Slipicevic A, Flørenes VA, Chibbar R, DeCoteau JF, Bilalovic N . Fli-1 expression in malignant melanoma. Histol Histopathol 2008; 23: 1309–1314.

    CAS  Google Scholar 

  103. Paula P, Barros-Silva JD, Ribeiro FR, Ramalho-Carvalho J, Jerónimo C, Henrique R et al. FLI1 is a novel ETS transcription factor involved in gene fusions in prostate cancer. Genes Chromosomes Cancer 2012; 51: 240–249.

    Google Scholar 

  104. Cuda J, Mirzamani N, Kantipudi R, Robbins J, Welsch MJ, Sundram UN . Diagnostic utility of Fli-1 and D2-40 in distinguishing atypical fibroxanthoma from angiosarcoma. Am J Dermatopathol 2013; 35: 316–318.

    Google Scholar 

  105. Brown JG, Folpe AL, Rao P, Lazar AJ, Paner GP, Gupta R et al. Primary vascular tumors and tumor-like lesions of the kidney: a clinicopathologic analysis of 25 cases. Am J Surg Pathol 2010; 34: 942–949.

    Google Scholar 

  106. Gill R, O'Donnell RJ, Horvai A . Utility of immunohistochemistry for endothelial markers in distinguishing epithelioid hemangioendothelioma from carcinoma metastatic to bone. Arch Pathol Lab Med 2009; 133: 967–972.

    CAS  Google Scholar 

  107. Nagano A, Ohno T, Shimizu K, Hara A, Yamamoto T, Kawai G et al. EWS/Fli-1 chimeric fusion gene upregulates vascular endothelial growth factor-A. Int J Cancer 2010; 126: 2790–2798.

    CAS  Google Scholar 

  108. Shaked Y, Cervi D, Neuman M, Chen L, Klement G, Michaud CR et al. The splenic microenvironment is a source of proangiogenesis/inflammatory mediators accelerating the expansion of murine erythroleukemic cells. Blood 2005; 105: 4500–4507.

    CAS  Google Scholar 

  109. Boro A, Prêtre K, Rechfeld F, Thalhammer V, Oesch S, Wachtel M et al. Small-molecule screen identifies modulators of EWS/FLI1 target gene expression and cell survival in Ewing's sarcoma. Int J Cancer 2012; 131: 2153–2164.

    CAS  Google Scholar 

  110. Grohar PJ, Griffin LB, Yeung C, Chen QR, Pommier Y, Khanna C et al. Ecteinascidin 743 interferes with the activity of EWS-FLI1 in Ewing sarcoma cells. Neoplasia 2011; 13: 145–153.

    CAS  Google Scholar 

  111. Erkizan HV, Kong Y, Merchant M, Schlottmann S, Barber-Rotenberg JS, Yuan L et al. A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma. Nat Med 2009; 15: 750–756.

    CAS  Google Scholar 

  112. Grohar PJ, Woldemichael GM, Griffin LB, Mendoza A, Chen QR, Yeung C et al. Identification of an inhibitor of the EWS-FLI1 oncogenic transcription factor by high-throughput screening. J Natl Cancer Inst 2011; 103: 962–978.

    CAS  Google Scholar 

  113. Li YJ, Zhao X, Vecchiarelli-Federico LM, Li Y, Datti A, Cheng Y et al. Drug-mediated inhibition of Fli-1 for the treatment of leukemia. Blood Cancer J 2012; 2: e54.

    Google Scholar 

  114. Bhatia S, Krailo MD, Chen Z, Burden L, Askin FB, Dickman PS et al. Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: a report from the Children's Oncology Group. Blood 2007; 109: 46–51.

    CAS  Google Scholar 

  115. Ladenstein R, Pötschger U, Le Deley MC, Whelan J, Paulussen M, Oberlin O et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 2010; 28: 3284–3291.

    CAS  Google Scholar 

  116. Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ et al. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide–a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol 2004; 22: 2873–2876.

    CAS  Google Scholar 

  117. Zhang J, Guo H, Zhang H, Wang H, Qian G, Fan X et al. Putative tumor suppressor miR-145 inhibits colon cancer cell growth by targeting oncogene Friend leukemia virus integration 1 gene. Cancer 2011; 117: 86–95.

    CAS  Google Scholar 

  118. Ban J, Jug G, Mestdagh P, Schwentner R, Kauer M, Aryee DN et al. Hsa-mir-145 is the top EWS-FLI1-repressed microRNA involved in a positive feedback loop in Ewing's sarcoma. Oncogene 2011; 30: 2173–2180.

    CAS  Google Scholar 

  119. Bujor AM, Haines P, Padilla C, Christmann RB, Junie M, Sampaio-Barros PD et al. Ciprofloxacin has antifibrotic effects in scleroderma fibroblasts via downregulation of Dnmt1 and upregulation of Fli1. Int J Mol Med 2012; 30: 1473–1480.

    CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Canadian Institute of Health Research to YB-D (MOP-110952), Canadian Breast Cancer Foundation to EZ, the Science and Technology Department of Guizhou Province innovation and project grants (6012, 4001) to YB-D.

Author information

Authors and Affiliations

  1. Department of Anatomy, Norman Bethune College of Medicine, Jilin University, Changchun, China

    Y Li

  2. Division of Biology, the Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, China

    H Luo, T Liu & Y Ben-David

  3. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    E Zacksenhaus & Y Ben-David

  4. Division of Advanced Diagnostics, Toronto General Research Institute—University Health Network, Toronto, Ontario, Canada

    E Zacksenhaus

Authors
  1. Y Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Zacksenhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Ben-David
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Ben-David.

Ethics declarations

Competing interests

These authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Luo, H., Liu, T. et al. The ets transcription factor Fli-1 in development, cancer and disease. Oncogene 34, 2022–2031 (2015). https://doi.org/10.1038/onc.2014.162

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.162

This article is cited by

Search

Advanced search

Quick links