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siRNA-mediated AML1/MTG8 depletion affects differentiation and proliferation-associated gene expression in t(8;21)-positive cell lines and primary AML blasts

Oncogene volume 25, pages 6067–6078 (2006)Cite this article

Abstract

The chromosomal translocation t(8;21) is associated with 10–15% of all cases of acute myeloid leukaemia (AML). The resultant fusion protein AML1/MTG8 interferes with haematopoietic gene expression and is an important regulator of leukaemogenesis. We studied the effects of small interfering RNA (siRNA)-mediated AML1/MTG8 depletion on global gene expression in t(8;21)-positive leukaemic cell lines and in primary AML blasts using cDNA arrays, oligonucleotide arrays and real-time reverse transcription–polymerase chain reaction (RT–PCR). Suppression of AML1/MTG8 results in the increased expression of genes associated with myeloid differentiation, such as AZU1, BPI, CTSG, LYZ and RNASE2 as well as of antiproliferative genes such as IGFBP7, MS4A3 and SLA both in blasts and in cell lines. Furthermore, expression levels of several genes affiliated with drug resistance or indicative of poor prognosis AML (BAALC, CD34, PRG2, TSPAN7) are affected by AML1/MTG8 depletion. In conclusion, siRNA-mediated suppression of AML1/MTG8 cause very similar changes in gene expression pattern in t(8;21)-positive cell lines and in primary AML blasts. Furthermore, the results suggest that the specific targeting of AML1/MTG8 function may be a promising approach for complementing existing treatment strategies.

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References

  • Alcalay M, Meani N, Gelmetti V, Fantozzi A, Fagioli M, Orleth A et al. (2003). J Clin Invest 112: 1751–1761.

  • Amann JM, Nip J, Strom DK, Lutterbach B, Harada H, Lenny N et al. (2001). Mol Cell Biol 21: 6470–6483.

  • Asou H, Tashiro S, Hamamoto K, Otsuji A, Kita K, Kamada N . (1991). Blood 77: 2031–2036.

  • Baesecke J, Schwieger M, Griesinger F, Schiedlmeier B, Wulf G, Trumper L et al. (2005). Leukemia Lymphoma 46: 265–272.

  • Baldus CD, Tanner SM, Kusewitt DF, Liyanarachchi S, Choi C, Caligiuri MA et al. (2003a). Exp Hematol 31: 1051–1056.

  • Baldus CD, Tanner SM, Ruppert AS, Whitman SP, Archer KJ, Marcucci G et al. (2003b). Blood 102: 1613–1618.

  • Banker DE, Radich J, Becker A, Kerkof K, Norwood T, Willman C et al. (1998). Clin Cancer Res 4: 3051–3062.

  • Barrett T, Suzek TO, Troup DB, Wilhite SE, Ngau WC, Ledoux P et al. (2005). Nucleic Acids Res 33: D562–D566.

  • Berwanger B, Hartmann O, Bergmann E, Bernard S, Nielsen D, Krause M et al. (2002). Cancer Cell 2: 377–386.

  • Bullinger L, Dohner K, Bair E, Frohling S, Schlenk RF, Tibshirani R et al. (2004). N Engl J Med 350: 1605–1616.

  • Burel SA, Harakawa N, Zhou L, Pabst T, Tenen DG, Zhang DE . (2001). Mol Cell Biol 21: 5577–5590.

  • Debernardi S, Lillington DM, Chaplin T, Tomlinson S, Amess J, Rohatiner A et al. (2003). Genes Chromosomes Cancer 37: 149–158.

  • Donato JL, Ko J, Kutok JL, Cheng T, Shirakawa T, Mao XQ et al. (2002). J Clin Invest 109: 51–58.

  • Erickson P, Gao J, Chang KS, Look T, Whisenant E, Raimondi S et al. (1992). Blood 80: 1825–1831.

  • Fliegauf M, Stock M, Berg T, Lubbert M . (2004). Oncogene 23: 9070–9081.

  • Follows GA, Tagoh H, Lefevre P, Hodge D, Morgan GJ, Bonifer C . (2003). EMBO J 22: 2798–2809.

  • Frank R, Zhang J, Uchida H, Meyers S, Hiebert SW, Nimer SD . (1995). Oncogene 11: 2667–2674.

  • Garwicz D, Lennartsson A, Jacobsen SE, Gullberg U, Lindmark A . (2005). Haematologica 90: 38–44.

  • Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci PG, Lazar MA . (1998). Mol Cell Biol 18: 7185–7191.

  • Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S et al. (2004). Genome Biol 5: R80.

  • Guenther MG, Jenner RG, Chevalier B, Nakamura T, Croce CM, Canaani E et al. (2005). Proc Natl Acad Sci USA 102: 8603–8608.

  • Heidenreich O, Krauter J, Riehle H, Hadwiger P, John M, Heil G et al. (2003). Blood 101: 3157–3163.

  • Heuser M, Wingen LU, Steinemann D, von Neuhoff GC, Tauscher M, Bullinger L et al. (2005). Haematologica 90: 1484–1492.

  • Hiebert SW, Downing JR, Lenny N, Meyers S . (1996). Curr Top Microbiol Immunol 211: 253–258.

  • Hildebrand D, Tiefenbach J, Heinzel T, Grez M, Maurer AB . (2001). J Biol Chem 276: 9889–9895.

  • Jakubowiak A, Pouponnot C, Berguido F, Frank R, Mao S, Massague J et al. (2000). J Biol Chem 275: 40282–40287.

  • Kusec R, Laczika K, Knobl P, Friedl J, Greinix H, Kahls P et al. (1994). Leukemia 8: 735–739.

  • Landberg G, Ostlund H, Nielsen NH, Roos G, Emdin S, Burger AM et al. (2001). Oncogene 20: 3497–3505.

  • Lausen J, Liu S, Fliegauf M, Lubbert M, Werner MH . (2006). Oncogene 25: 1349–1357.

  • Lebigot I, Gardellin P, Lefebvre L, Beug H, Ghysdael J, Quang CT . (2003). Blood 102: 4555–4562.

  • Lennartsson A, Pieters K, Ullmark T, Vidovic K, Gullberg U . (2003). Biochem Biophys Res Commun 311: 853–863.

  • Linggi B, Muller-Tidow C, van de Locht L, Hu M, Nip J, Serve H et al. (2002). Nat Med 8: 743–750.

  • Lopez-Bermejo A, Buckway CK, Devi GR, Hwa V, Plymate SR, Oh Y et al. (2000). Endocrinology 141: 4072–4080.

  • Lutterbach B, Westendorf JJ, Linggi B, Patten A, Moniwa M, Davie JR et al. (1998). Mol Cell Biol 18: 7176–7184.

  • Martinez N, Drescher B, Riehle H, Cullmann C, Vornlocher HP, Ganser A et al. (2004). BMC Cancer 4: 44.

  • Matozaki S, Nakagawa T, Kawaguchi R, Aozaki R, Tsutsumi M, Murayama T et al. (1995). Br J Haematol 89: 805–811.

  • Melnick AM, Westendorf JJ, Polinger A, Carlile GW, Arai S, Ball HJ et al. (2000). Mol Cell Biol 20: 2075–2086.

  • Meyers S, Downing JR, Hiebert SW . (1993). Mol Cell Biol 13: 6336–6345.

  • Miyamoto T, Weissman IL, Akashi K . (2000). Proc Natl Acad Sci USA 97: 7521–7526.

  • Miyoshi H, Kozu T, Shimizu K, Enomoto K, Maseki N, Kaneko Y et al. (1993). EMBO J 12: 2715–2721.

  • Mori H, Colman SM, Xiao Z, Ford AM, Healy LE, Donaldson C et al. (2002). Proc Natl Acad Sci USA 99: 8242–8247.

  • Morohoshi F, Mitani S, Mitsuhashi N, Kitabayashi I, Takahashi E, Suzuki M et al. (2000). Gene 241: 287–295.

  • Mulloy JC, Cammenga J, MacKenzie KL, Berguido FJ, Moore MA, Nimer SD . (2002). Blood 99: 15–23.

  • Mulloy JC, Jankovic V, Wunderlich M, Delwel R, Cammenga J, Krejci O et al. (2005). Proc Natl Acad Sci USA 102: 4016–4021.

  • Mutaguchi K, Yasumoto H, Mita K, Matsubara A, Shiina H, Igawa M et al. (2003). Cancer Res 63: 7717–7723.

  • Nisson PE, Watkins PC, Sacchi N . (1992). Cancer Genet Cytogenet 63: 81–88.

  • Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E, Rosenfeld RG . (1996). J Biol Chem 271: 30322–30325.

  • Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR . (1996). Cell 84: 321–330.

  • Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G et al. (2001). Nat Med 7: 444–451.

  • Philippar U, Schratt G, Dieterich C, Muller JM, Galgoczy P, Engel FB et al. (2004). Mol Cell 16: 867–880.

  • Puccetti E, Obradovic D, Beissert T, Bianchini A, Washburn B, Chiaradonna F et al. (2002). Cancer Res 62: 7050–7058.

  • Rhoades KL, Hetherington CJ, Harakawa N, Yergeau DA, Zhou L, Liu LQ et al. (2000). Blood 96: 2108–2115.

  • Roche S, Alonso G, Kazlauskas A, Dixit VM, Courtneidge SA, Pandey A . (1998). Curr Biol 8: 975–978.

  • Ross ME, Mahfouz R, Onciu M, Liu HC, Zhou X, Song G et al. (2004). Blood 104: 3679–3687.

  • Sundstrom C, Nilsson K . (1976). Int J Cancer 17: 565–577.

  • Swisshelm K, Ryan K, Tsuchiya K, Sager R . (1995). Proc Natl Acad Sci USA 92: 4472–4476.

  • Tonks A, Pearn L, Tonks AJ, Pearce L, Hoy T, Phillips S et al. (2003). Blood 101: 624–632.

  • Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn-Khosrovani S, Boer JM et al. (2004). N Engl J Med 350: 1617–1628.

  • Vangala RK, Heiss-Neumann MS, Rangatia JS, Singh SM, Schoch C, Tenen DG et al. (2003). Blood 101: 270–277.

  • Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM . (1998). Proc Natl Acad Sci USA 95: 10860–10865.

  • Wang Q, Stacy T, Binder M, Marin-Padilla M, Sharpe AH, Speck NA . (1996). Proc Natl Acad Sci USA 93: 3444–3449.

  • Weiss J, Olsson I . (1987). Blood 69: 652–659.

  • Westendorf JJ, Yamamoto CM, Lenny N, Downing JR, Selsted ME, Hiebert SW . (1998). Mol Cell Biol 18: 322–333.

  • Yagi T, Morimoto A, Eguchi M, Hibi S, Sako M, Ishii E et al. (2003). Blood 102: 1849–1856.

  • Yamanaka Y, Wilson EM, Rosenfeld RG, Oh Y . (1997). J Biol Chem 272: 30729–30734.

  • Yergeau DA, Hetherington CJ, Wang Q, Zhang P, Sharpe AH, Binder M et al. (1997). Nat Genet 15: 303–306.

  • Zhang J, Kalkum M, Yamamura S, Chait BT, Roeder RG . (2004). Science 305: 1286–1289.

  • Zimmer M, Medcalf RL, Fink TM, Mattmann C, Lichter P, Jenne DE . (1992). Proc Natl Acad Sci USA 89: 8215–8219.

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Acknowledgements

We thank Tracy Chaplin for her expert processing of the Affymetrix chips, Gael Molloy for helpful advice and Kerstin Görlich for excellent technical assistance. This work was supported by grants from the Deutsche Krebshilfe (10-2104-He2) and the Wilhelm-Sander-Stiftung (2003.169.1) to JK and OH and by the Kompetenznetz ‘Akute und chronische Leukämien’ (BMBF 01GI9974) to AN.

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Author notes

  1. C Cullmann

    Present address: Research Group Molecular Therapy of Virus-Associated Cancers, German Cancer Research Center, Heidelberg, Germany

  2. J Dunne and C Cullmann: These authors equally contributed to the work.

Authors and Affiliations

  1. Cancer Research UK Medical Oncology Laboratory, Barts and the London School of Medicine, London, UK

    J Dunne, S Debernardi, S Skoulakis & B D Young

  2. Department of Molecular Biology, Interfaculty Institute of Cell Biology, Faculty of Biology, Eberhard Karls University Tuebingen, Germany

    C Cullmann, N Martinez Soria & O Heidenreich

  3. Department of Haematology, Oncology and Immunology, University Hospital Marburg, Germany

    M Ritter & A Neubauer

  4. Department of Haematology, Haemostaseology and Oncology, Hannover Medical School, Hannover, Germany

    B Drescher & J Krauter

  5. Institute for Medical Biometry and Epidemiology, Philipps University Marburg, Germany

    O Hartmann

  6. Institute for Molecular Biology and Tumour Research, Philipps University Marburg, Germany

    M Krause

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Correspondence to O Heidenreich.

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Dunne, J., Cullmann, C., Ritter, M. et al. siRNA-mediated AML1/MTG8 depletion affects differentiation and proliferation-associated gene expression in t(8;21)-positive cell lines and primary AML blasts. Oncogene 25, 6067–6078 (2006). https://doi.org/10.1038/sj.onc.1209638

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  • DOI: https://doi.org/10.1038/sj.onc.1209638

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