Abstract
Inversion(16) is one of the most frequent chromosomal translocations found in acute myeloid leukemia (AML), occurring in over 8% of AML cases. This translocation results in a protein product that fuses the first 165 amino acids of core binding factor beta to the coiled-coil region of a smooth muscle myosin heavy chain (CBFbeta/SMMHC). CBFbeta interacts with AML1 to form a heterodimer that binds DNA; this interaction increases the affinity of AML1 for DNA. The CBFbeta/SMMHC fusion protein cooperates with AML1 to repress the transcription of AML1-regulated genes. We show that CBFbeta/SMMHC contains a repression domain in the C-terminal 163 amino acids of the SMMHC region that is required for inv(16)-mediated transcriptional repression. This minimal repression domain is sufficient for the association of CBFbeta/SMMHC with the mSin3A corepressor. In addition, the inv(16) fusion protein specifically associates with histone deacetylase 8 (HDAC8). inv(16)-mediated repression is sensitive to HDAC inhibitors. We propose a model whereby the inv(16) fusion protein associates with AML1 to convert AML1 into a constitutive transcriptional repressor.
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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3T3 Cells
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Animals
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COS Cells
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Chromosome Inversion*
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins / chemistry*
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DNA-Binding Proteins / metabolism
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Dimerization
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Gene Deletion
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Histone Deacetylases / metabolism
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Humans
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Immunoblotting
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism*
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Mice
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Mutation
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Myosin Heavy Chains / chemistry*
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Oncogene Proteins, Fusion / metabolism*
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Plasmids / metabolism
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Protein Binding
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Protein Structure, Tertiary
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Proto-Oncogene Proteins*
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Recombinant Fusion Proteins / metabolism
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Repressor Proteins / metabolism
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Saccharomyces cerevisiae Proteins*
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Sin3 Histone Deacetylase and Corepressor Complex
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Smooth Muscle Myosins / chemistry*
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Subcellular Fractions
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Transcription Factors / chemistry*
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Transcription Factors / metabolism*
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Transcription, Genetic
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Transfection
Substances
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins
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Oncogene Proteins, Fusion
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Proto-Oncogene Proteins
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RUNX1 protein, human
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Recombinant Fusion Proteins
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Repressor Proteins
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Runx1 protein, mouse
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SIN3 protein, S cerevisiae
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SIN3A transcription factor
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Saccharomyces cerevisiae Proteins
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Transcription Factors
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inv(16) fusion protein, human
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HDAC8 protein, human
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Histone Deacetylases
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Sin3 Histone Deacetylase and Corepressor Complex
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Smooth Muscle Myosins
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Myosin Heavy Chains