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
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Acute Disease
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Amino Acid Sequence
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Basic Helix-Loop-Helix Transcription Factors
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CREB-Binding Protein
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Cell Line
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Cell Line, Tumor
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Conserved Sequence
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Silencing*
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HeLa Cells
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Hematopoietic Stem Cells / physiology
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Humans
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Jurkat Cells
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Leukemia, Myeloid / genetics
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Leukemia, Myeloid / metabolism*
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Molecular Sequence Data
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Nuclear Proteins / metabolism
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Protein Binding
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Protein Structure, Tertiary
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RUNX1 Translocation Partner 1 Protein
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TCF Transcription Factors
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Trans-Activators / metabolism
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Transcription Factor 7-Like 2 Protein
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Activation
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Translocation, Genetic
Substances
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AML1-ETO fusion protein, human
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Basic Helix-Loop-Helix Transcription Factors
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins
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Nuclear Proteins
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Oncogene Proteins, Fusion
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RUNX1 Translocation Partner 1 Protein
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TCF Transcription Factors
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TCF3 protein, human
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TCF7L2 protein, human
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Trans-Activators
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Transcription Factor 7-Like 2 Protein
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Transcription Factors
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TCF12 protein, human
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CREB-Binding Protein
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CREBBP protein, human