ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors

Bart Lutterbach, Jennifer J Westendorf, Bryan Linggi, Andrea Patten, Mariko Moniwa, James R. Davie, Khanh D. Huynh, Vivian J. Bardwell, Robert M. Lavinsky, Michael G. Rosenfeld, Christopher Glass, Edward Seto, Scott W. Hiebert

Research output: Contribution to journalArticle

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Abstract

t(8;21) is one of the most frequent translocations associated with acute myeloid leukemia. It produces a chimeric protein, acute myeloid leukemia-1 (AML-1)-eight-twenty-one (ETO), that contains the amino-terminal DNA binding domain of the AML-1 transcriptional regulator fused to nearly all of ETO. Here we demonstrate that ETO interacts with the nuclear receptor corepressor N-CoR, the mSin3 corepressors, and histone deacetylases. Endogenous ETO also cosediments on sucrose gradients with mSin3A, N-CoR, and histone deacetylases, suggesting that it is a component of one or more corepressor complexes. Deletion mutagenesis indicates that ETO interacts with mSin3A independently of its association with N-CoR. Single amino acid mutations that impair the ability of ETO to interact with the central portion of N-CoR affect the ability of the t(8;21) fusion protein to repress transcription. Finally, AML-1/ETO associates with histone deacetylase activity and a histone deacetylase inhibitor impairs the ability of the fusion protein to repress transcription. Thus, t(8;21) fuses a component of a corepressor complex to AML-1 to repress transcription.

Original languageEnglish (US)
Pages (from-to)7176-7184
Number of pages9
JournalMolecular and Cellular Biology
Volume18
Issue number12
StatePublished - Dec 1998
Externally publishedYes

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Co-Repressor Proteins
Acute Myeloid Leukemia
Histone Deacetylases
Leukemia
Core Binding Factor Alpha 2 Subunit
Histone Deacetylase Inhibitors
Mutagenesis
Sucrose
Proteins
Amino Acids
Mutation
DNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Lutterbach, B., Westendorf, J. J., Linggi, B., Patten, A., Moniwa, M., Davie, J. R., ... Hiebert, S. W. (1998). ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Molecular and Cellular Biology, 18(12), 7176-7184.

ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. / Lutterbach, Bart; Westendorf, Jennifer J; Linggi, Bryan; Patten, Andrea; Moniwa, Mariko; Davie, James R.; Huynh, Khanh D.; Bardwell, Vivian J.; Lavinsky, Robert M.; Rosenfeld, Michael G.; Glass, Christopher; Seto, Edward; Hiebert, Scott W.

In: Molecular and Cellular Biology, Vol. 18, No. 12, 12.1998, p. 7176-7184.

Research output: Contribution to journalArticle

Lutterbach, B, Westendorf, JJ, Linggi, B, Patten, A, Moniwa, M, Davie, JR, Huynh, KD, Bardwell, VJ, Lavinsky, RM, Rosenfeld, MG, Glass, C, Seto, E & Hiebert, SW 1998, 'ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors', Molecular and Cellular Biology, vol. 18, no. 12, pp. 7176-7184.
Lutterbach, Bart ; Westendorf, Jennifer J ; Linggi, Bryan ; Patten, Andrea ; Moniwa, Mariko ; Davie, James R. ; Huynh, Khanh D. ; Bardwell, Vivian J. ; Lavinsky, Robert M. ; Rosenfeld, Michael G. ; Glass, Christopher ; Seto, Edward ; Hiebert, Scott W. / ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. In: Molecular and Cellular Biology. 1998 ; Vol. 18, No. 12. pp. 7176-7184.
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abstract = "t(8;21) is one of the most frequent translocations associated with acute myeloid leukemia. It produces a chimeric protein, acute myeloid leukemia-1 (AML-1)-eight-twenty-one (ETO), that contains the amino-terminal DNA binding domain of the AML-1 transcriptional regulator fused to nearly all of ETO. Here we demonstrate that ETO interacts with the nuclear receptor corepressor N-CoR, the mSin3 corepressors, and histone deacetylases. Endogenous ETO also cosediments on sucrose gradients with mSin3A, N-CoR, and histone deacetylases, suggesting that it is a component of one or more corepressor complexes. Deletion mutagenesis indicates that ETO interacts with mSin3A independently of its association with N-CoR. Single amino acid mutations that impair the ability of ETO to interact with the central portion of N-CoR affect the ability of the t(8;21) fusion protein to repress transcription. Finally, AML-1/ETO associates with histone deacetylase activity and a histone deacetylase inhibitor impairs the ability of the fusion protein to repress transcription. Thus, t(8;21) fuses a component of a corepressor complex to AML-1 to repress transcription.",
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AU - Davie, James R.

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