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

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
Mol Cell Biol. 1998 18 (12): 7176-84

PMID: 9819404 · PMCID: PMC109299 · DOI:10.1128/mcb.18.12.7176

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.

MeSH Terms (18)

Cell Line Chromosomes, Human, Pair 8 Chromosomes, Human, Pair 21 Core Binding Factor Alpha 2 Subunit DNA-Binding Proteins Histone Deacetylases Humans Leukemia, Myeloid Nuclear Proteins Nuclear Receptor Co-Repressor 1 Precipitin Tests Proto-Oncogene Proteins Recombinant Fusion Proteins Repressor Proteins RUNX1 Translocation Partner 1 Protein Saccharomyces cerevisiae Proteins Transcription Factors Translocation, Genetic

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