E protein silencing by the leukemogenic AML1-ETO fusion protein

Science. 2004 Aug 27;305(5688):1286-9. doi: 10.1126/science.1097937.

Abstract

The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 15% of acute myeloid leukemia (AML) cases. This study shows that AML1-ETO, as well as ETO, inhibits transcriptional activation by E proteins through stable interactions that preclude recruitment of p300/CREB-binding protein (CBP) coactivators. These interactions are mediated by a conserved ETO TAF4 homology domain and a 17-amino acid p300/CBP and ETO target motif within AD1 activation domains of E proteins. In t(8;21) leukemic cells, very stable interactions between AML1-ETO and E proteins underlie a t(8;21) translocation-specific silencing of E protein function through an aberrant cofactor exchange mechanism. These studies identify E proteins as AML1-ETO targets whose dysregulation may be important for t(8;21) leukemogenesis, as well as an E protein silencing mechanism that is distinct from that associated with differentiation-inhibitory proteins.

MeSH terms

  • Acute Disease
  • Amino Acid Sequence
  • Basic Helix-Loop-Helix Transcription Factors
  • CREB-Binding Protein
  • Cell Line
  • Cell Line, Tumor
  • Conserved Sequence
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Silencing*
  • HeLa Cells
  • Hematopoietic Stem Cells / physiology
  • Humans
  • Jurkat Cells
  • Leukemia, Myeloid / genetics
  • Leukemia, Myeloid / metabolism*
  • Molecular Sequence Data
  • Nuclear Proteins / metabolism
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • RUNX1 Translocation Partner 1 Protein
  • TCF Transcription Factors
  • Trans-Activators / metabolism
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation
  • Translocation, Genetic

Substances

  • AML1-ETO fusion protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • RUNX1 Translocation Partner 1 Protein
  • TCF Transcription Factors
  • TCF3 protein, human
  • TCF7L2 protein, human
  • Trans-Activators
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors
  • TCF12 protein, human
  • CREB-Binding Protein
  • CREBBP protein, human