Abstract
The leukemia-associated fusion gene AML1/MDS1/EVI1 (AME) encodes a chimeric transcription factor that results from the (3;21)(q26;q22) translocation. This translocation is observed in patients with therapy-related myelodysplastic syndrome (MDS), with chronic myelogenous leukemia during the blast crisis (CML-BC), and with de novo or therapy-related acute myeloid leukemia (AML). AME is obtained by in-frame fusion of the AML1 and MDS1/EVI1 genes. We have previously shown that AME is a transcriptional repressor that induces leukemia in mice. In order to elucidate the role of AME in leukemic transformation, we investigated the interaction of AME with the transcription co-regulator CtBP1 and with members of the histone deacetylase (HDAC) family. In this report, we show that AME physically interacts in vivo with CtBP1 and HDAC1 and that these co-repressors require distinct regions of AME for interaction. By using reporter gene assays, we demonstrate that AME represses gene transcription by CtBP1-dependent and CtBP1-independent mechanisms. Finally, we show that the interaction between AME and CtBP1 is biologically important and is necessary for growth upregulation and abnormal differentiation of the murine hematopoietic precursor cell line 32Dc13 and of murine bone marrow progenitors.
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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Acute Disease
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Alcohol Oxidoreductases
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Animals
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Binding Sites
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Bone Marrow Cells / cytology
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Bone Marrow Cells / metabolism
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Cell Differentiation
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Cell Division
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Cell Line
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Cell Nucleus / metabolism
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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 / physiology*
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Gene Expression Regulation, Leukemic*
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Hematopoietic Cell Growth Factors / pharmacology
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Hematopoietic Stem Cells / metabolism*
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Histone Deacetylase 1
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Histone Deacetylases / metabolism
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Humans
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Leukemia, Myeloid / genetics
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Mice
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Microscopy, Confocal
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Oncogene Proteins, Fusion / chemistry
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / physiology*
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Phosphoproteins / chemistry
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Phosphoproteins / physiology*
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Protein Binding
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Protein Interaction Mapping
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Repressor Proteins / chemistry
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Repressor Proteins / genetics
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Repressor Proteins / physiology*
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Transcription, Genetic
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Transfection
Substances
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AML1-MDS1-EVI1 fusion protein, human
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins
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Hematopoietic Cell Growth Factors
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Oncogene Proteins, Fusion
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Phosphoproteins
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Recombinant Fusion Proteins
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Repressor Proteins
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Alcohol Oxidoreductases
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C-terminal binding protein
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HDAC1 protein, human
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Histone Deacetylase 1
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Histone Deacetylases