Abstract
Nuclear receptor corepressor (CoR)-histone deacetylase (HDAC) complex recruitment is indispensable for the biological activities of the retinoic acid receptor fusion proteins of acute promyelocytic leukemias. We report here that ETO (eight-twenty-one or MTG8), which is fused to the acute myelogenous leukemia 1 (AML1) transcription factor in t(8;21) AML, interacts via its zinc finger region with a conserved domain of the corepressors N-CoR and SMRT and recruits HDAC in vivo. The fusion protein AML1-ETO retains the ability of ETO to form stable complexes with N-CoR/SMRT and HDAC. Deletion of the ETO C terminus abolishes CoR binding and HDAC recruitment and severely impairs the ability of AML1-ETO to inhibit differentiation of hematopoietic precursors. These data indicate that formation of a stable complex with CoR-HDAC is crucial to the activation of the leukemogenic potential of AML1 by ETO and suggest that aberrant recruitment of corepressor complexes is a general mechanism of leukemogenesis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Cell Differentiation / genetics
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Chromosomes, Human, Pair 21 / genetics
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Chromosomes, Human, Pair 8 / genetics
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins / genetics*
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Hematopoietic Stem Cells / metabolism
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Histone Deacetylases / genetics*
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Humans
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Leukemia, Myeloid / genetics*
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Models, Biological
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Nuclear Proteins / genetics*
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Nuclear Receptor Co-Repressor 1
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Protein Binding / genetics
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Proto-Oncogene Proteins*
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RUNX1 Translocation Partner 1 Protein
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Receptors, Retinoic Acid / genetics
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Recombinant Fusion Proteins / genetics*
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Repressor Proteins / genetics*
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Transcription Factors / genetics*
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Tumor Cells, Cultured
Substances
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins
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NCOR1 protein, human
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Nuclear Proteins
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Nuclear Receptor Co-Repressor 1
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Proto-Oncogene Proteins
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RUNX1 Translocation Partner 1 Protein
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RUNX1 protein, human
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RUNX1T1 protein, human
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Receptors, Retinoic Acid
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Recombinant Fusion Proteins
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Repressor Proteins
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Transcription Factors
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Histone Deacetylases