ETO, a target of t(8;21) in acute leukemia, makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain

Mol Cell Biol. 2001 Oct;21(19):6470-83. doi: 10.1128/mcb.21.19.6470-6483.2001.

Abstract

t(8;21) and t(16;21) create two fusion proteins, AML-1-ETO and AML-1-MTG16, respectively, which fuse the AML-1 DNA binding domain to putative transcriptional corepressors, ETO and MTG16. Here, we show that distinct domains of ETO contact the mSin3A and N-CoR corepressors and define two binding sites within ETO for each of these corepressors. In addition, of eight histone deacetylases (HDACs) tested, only the class I HDACs HDAC-1, HDAC-2, and HDAC-3 bind ETO. However, these HDACs bind ETO through different domains. We also show that the murine homologue of MTG16, ETO-2, is also a transcriptional corepressor that works through a similar but distinct mechanism. Like ETO, ETO-2 interacts with N-CoR, but ETO-2 fails to bind mSin3A. Furthermore, ETO-2 binds HDAC-1, HDAC-2, and HDAC-3 but also interacts with HDAC-6 and HDAC-8. In addition, we show that expression of AML-1-ETO causes disruption of the cell cycle in the G(1) phase. Disruption of the cell cycle required the ability of AML-1-ETO to repress transcription because a mutant of AML-1-ETO, Delta469, which removes the majority of the corepressor binding sites, had no phenotype. Moreover, treatment of AML-1-ETO-expressing cells with trichostatin A, an HDAC inhibitor, restored cell cycle control. Thus, AML-1-ETO makes distinct contacts with multiple HDACs and an HDAC inhibitor biologically inactivates this fusion protein.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Line
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / physiology
  • Enzyme Inhibitors / pharmacology
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases / metabolism*
  • Hydroxamic Acids / pharmacology
  • Leukemia, Myelomonocytic, Acute / genetics*
  • Mice
  • Models, Genetic
  • Molecular Sequence Data
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology
  • Nuclear Receptor Co-Repressor 1
  • Oncogene Proteins, Fusion / antagonists & inhibitors
  • Oncogene Proteins, Fusion / physiology*
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins*
  • RUNX1 Translocation Partner 1 Protein
  • Repressor Proteins / metabolism*
  • Sequence Homology, Amino Acid
  • Sin3 Histone Deacetylase and Corepressor Complex
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / chemistry*
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology*
  • Transcription, Genetic
  • Translocation, Genetic

Substances

  • AML1-ETO fusion protein, human
  • Cbfa2t3 protein, mouse
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • NCOR1 protein, human
  • Ncor1 protein, mouse
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 1
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • RUNX1 Translocation Partner 1 Protein
  • RUNX1T1 protein, human
  • Repressor Proteins
  • SIN3A transcription factor
  • Transcription Factors
  • trichostatin A
  • Histone Deacetylases
  • Sin3 Histone Deacetylase and Corepressor Complex