Abstract
The chromosomal translocations found in acute myelogenous leukemia (AML) generate oncogenic fusion transcription factors with aberrant transcriptional regulatory properties. Although therapeutic targeting of most leukemia fusion proteins remains elusive, the posttranslational modifications that control their function could be targetable. We found that AML1-ETO, the fusion protein generated by the t(8;21) translocation, is acetylated by the transcriptional coactivator p300 in leukemia cells isolated from t(8;21) AML patients, and that this acetylation is essential for its self-renewal-promoting effects in human cord blood CD34(+) cells and its leukemogenicity in mouse models. Inhibition of p300 abrogates the acetylation of AML1-ETO and impairs its ability to promote leukemic transformation. Thus, lysine acetyltransferases represent a potential therapeutic target in AML.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Animals
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Cell Line
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Cell Line, Tumor
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Cell Transformation, Neoplastic*
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Core Binding Factor Alpha 2 Subunit / chemistry
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Core Binding Factor Alpha 2 Subunit / metabolism*
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E1A-Associated p300 Protein / antagonists & inhibitors
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E1A-Associated p300 Protein / metabolism*
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Fetal Blood / cytology
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Gene Expression Profiling
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Hematopoietic Stem Cells / cytology*
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Hematopoietic Stem Cells / physiology
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Humans
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Leukemia, Myeloid, Acute / metabolism*
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Leukemia, Myeloid, Acute / pathology
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Lysine / metabolism*
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Mice
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Mice, Inbred C57BL
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Mutant Proteins / metabolism
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Oncogene Proteins, Fusion / chemistry
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Oncogene Proteins, Fusion / metabolism*
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Preleukemia / metabolism
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Preleukemia / pathology
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Protein Binding
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Protein Interaction Domains and Motifs
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Protein Processing, Post-Translational
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RUNX1 Translocation Partner 1 Protein
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Transcriptional Activation
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Tumor Cells, Cultured
Substances
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AML1-ETO fusion protein, human
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Core Binding Factor Alpha 2 Subunit
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Mutant Proteins
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Oncogene Proteins, Fusion
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RUNX1 Translocation Partner 1 Protein
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E1A-Associated p300 Protein
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EP300 protein, human
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Lysine