Abstract
A 117 bp fragment of the human ELA2 promoter has been characterized that can act as a minimal promoter for the expression of neutrophil elastase. Chromatin immunoprecipitation and siRNAs revealed that expression of ELA2 is regulated by the acute myeloid human leukemia 1 protein (AML1), C/EBPα, PU.1 and c-Myb transcription factors. ELA2 has also been investigated as a possible target of the leukemic fusion protein AML1-ETO resulting from the t(8;21) chromosomal translocation. AML1-ETO, like AML1, binds the ELA2 promoter in the myeloid cell lines Kasumi-1 and U937, but unexpectedly fails to significantly alter expression of ELA2. Although AML1-ETO downregulates the expression of C/EBPα, changes in C/EBPα expression do not correlate with changes in the expression of ELA2. Our observations indicate that AML1-ETO may not be a constitutive repressor of gene expression in every case in which it can associate with DNA, either on its own or in conjunction with C/EBPα. Since neither ETO nor AML1-ETO are typically expressed in hematopoietic progenitors, we hypothesize that it is the interactions between AML1-ETO and regulatory cofactors in disease-state cells that alter gene expression programs during hematopoiesis. These protein–protein interactions may not require simultaneous DNA binding by AML1-ETO for the deleterious effects of the fusion protein to be realized.
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References
Amann JM, Nip J, Strom DK, Lutterbach B, Harada H, Lenny N et al. (2001). Mol Cell Biol 21: 6470–6483.
Ancliff PJ, Gale RE, Liesner R, Hann IM, Linch DC . (2001). Blood 98: 2645–2650.
Banker DE, Radich J, Becker A, Kerkof K, Norwood T, Willman C et al. (1998). Clin Cancer Res 4: 3051–3062.
Boyd KE, Wells J, Gutman J, Bartley SM, Farnham PJ . (1998). Proc Natl Acad Sci 95: 13887–13892.
Burel SA, Harakawa N, Zhou L, Pabst T, Tenen DG, Zhang DE . (2001). Mol Cell Biol 21: 5577–5590.
Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA et al. (2000). Blood 96: 2317–2322.
Erickson P, Gao J, Chang K, 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.
Fouret P, du Bois R, Bernaudin J, Takahashi H, Ferrans V, Crystal R . (1989). J Exp Med 169: 833–845.
Friedman AD . (2002). Oncogene 21: 3377–3390.
Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci PG, Lazar MA . (1998). Mol Cell Biol 18: 7185–7191.
Heidenreich O, Krauter J, Riehle H, Hadwiger P, John M, Heil G et al. (2003). Blood 101: 3157–3163.
Hildebrand D, Tiefenbach J, Heinzel T, Grez M, Maurer AB . (2001). J Biol Chem 276: 9889–9895.
Hohaus S, Petrovick MS, Voso MT, Sun Z, Zhang DE, Tenen DG . (1995). Mol Cell Biol 15: 5830–5845.
Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC . (1999). Nat Genet 23: 433–436.
Hug BA, Lazar MA . (2004). Oncogene 23: 4270–4274.
Iwama A, Osawa M, Hirasawa R, Uchiyama N, Kaneko S, Onodera M et al. (2002). J Exp Med 195: 547–558.
Lane AA, Ley TJ . (2003). Cell 115: 305–318.
Lane AA, Ley TJ . (2005). Mol Cell Biol 25: 23–33.
Lausen J, Cho S, Liu S, Werner MH . (2004). J Biol Chem 279: 49281–49288.
Li F-Q, Person RE, Takemaru K-I, Williams K, Meade-White K, Ozsahin AH et al. (2004). J Biol Chem 279: 2873–2884.
Linggi B, Muller-Tidow C, van de Locht L, Hu M, Nip J, Serve H et al. (2002). Nat Med 8: 743–750.
Liu S, Spinner DS, Schmidt MM, Danielsson JA, Wang S, Schmidt J . (2000). J Biol Chem 275: 41364–41368.
Look AT . (1997). Science 278: 1059–1064.
Lutterbach B, Hiebert SW . (2000). Gene 245: 223–235.
Lutterbach B, Westendorf JJ, Linggi B, Isaac S, Seto E, Hiebert SW . (2000). J Biol Chem 275: 651–656.
Lutterbach B, Westendorf JJ, Linggi B, Patten A, Moniwa M, Davie JR et al. (1998). Mol Cell Biol 18: 7176–7184.
Meyers S, Lenny N, Hiebert S . (1995). Mol Cell Biol 15: 1974–1982.
Michaud J, Scott HS, Escher R . (2003). Cancer Invest 21: 105–136.
Minucci S, Maccarana M, Cioce M, deLuca P, Gelmetti V, Segalla S et al. (2000). Mol Cell 5: 811–820.
Miyoshi H, Kozu T, Shimizu K, Enomoto K, Maseki N, Kaneko Y et al. (1993). EMBO J 12: 2715–2721.
Miyoshi H, Shimizu K, Kozu T, Maseki N, Kaneko Y, Ohki M . (1991). Proc Natl Acad Sci 88: 10431–10434.
Nuchprayoon I, Meyers S, Scott LM, Suzow J, Hiebert S, Friedman AD . (1994). Mol Cell Biol 14: 5558–5568.
Nuchprayoon I, Shang J, Simkevich CP, Luo M, Rosmarin AG, Friedman AD . (1999). J Biol Chem 274: 1085–1091.
Nuchprayoon I, Simkevich CP, Luo M, Friedman AD, Rosmarin AG . (1997). Blood 89: 4546–4554.
Oelgeschlager M, Nuchprayoon I, Luscher B, Friedman A . (1996). Mol Cell Biol 16: 4717–4725.
Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G et al. (2001). Nat Med 7: 444–445.
Peterson LF, Zhang DE . (2004). Oncogene 23: 4255–4262.
Petrovick MS, Hiebert SW, Friedman AD, Hetherington CJ, Tenen DG, Zhang DE . (1998). Mol Cell Biol 18: 3915–3925.
Shimada H, Ichikawa H, Nakamura S, Katsu R, Iwasa M, Kitabayashi I et al. (2000). Blood 96: 655–663.
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 95: 10860–10865.
Westendorf JJ, Yamamoto CM, Lenny N, Downing JR, Selsted ME, Hiebert SW . (1998). Mol Cell Biol 18: 322–333.
Wildonger J, Mann RS . (2005). Development 132: 2263–2272.
Yan M, Burel SA, Peterson LF, Kanbe E, Iwasaki I, Boyapati A et al. (2004). Proc Natl Acad Sci USA 49: 17186–17191.
Zhang D, Hetherington C, Meyers S, Rhoades K, Larson C, Chen H et al. (1996). Mol Cell Biol 16: 1231–1240.
Zhang J, Hug BA, Huang EY, Chen CW, Gelmetti V, Maccarana M et al. (2001). Mol Cell Biol 21: 156–163.
Zhang J, Kalkum M, Yamamura S, Chait BT, Roeder RG . (2004). Science 305: 1286–1289.
Acknowledgements
This work was supported in part by a fellowship from the Deutsche Forschungsgemeinschaft (LA 1389/1-1) (to JL) and by the Specialized Center for Research Grant from the Leukemia and Lymphoma Society (to MHW). MHW is a Distinguished Young Scholar of the W M Keck Foundation. We thank S Hiebert, N Timchenko, EP Reddy, MJ Klemsz and S Nimer for providing expression and reporter vectors and T Berg and M Lübbert for sharing AML1-ETO microarray data prior to publication. ML is supported by the German José Carreras Foundation (00/14).
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Lausen, J., Liu, S., Fliegauf, M. et al. ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO. Oncogene 25, 1349–1357 (2006). https://doi.org/10.1038/sj.onc.1209181
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DOI: https://doi.org/10.1038/sj.onc.1209181
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