Abstract
Stimulation of transcriptional elongation is a key activity of leukemogenic MLL fusion proteins. Here, we provide evidence that MLL-ENL also inhibits Polycomb-mediated silencing as a prerequisite for efficient transformation. Biochemical studies identified ENL as a scaffold that contacted the elongation machinery as well as the Polycomb repressive complex 1 (PRC1) component CBX8. These interactions were mutually exclusive in vitro, corresponding to an antagonistic behavior of MLL-ENL and CBX8 in vivo. CBX8 inhibited elongation in a specific reporter assay, and this effect was neutralized by direct association with ENL. Correspondingly, CBX8-binding-defective MLL-ENL could not fully activate gene loci necessary for transformation. Finally, we demonstrate dimerization of MLL-ENL as a neomorphic activity that may augment Polycomb inhibition and transformation.
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Transformation, Neoplastic
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Dimerization
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HEK293 Cells
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / metabolism
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Histone-Lysine N-Methyltransferase
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Humans
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Myeloid-Lymphoid Leukemia Protein / genetics
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Myeloid-Lymphoid Leukemia Protein / metabolism*
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Polycomb Repressive Complex 1 / antagonists & inhibitors
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Polycomb Repressive Complex 1 / genetics
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Polycomb Repressive Complex 1 / metabolism*
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Protein Binding
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RNA Interference
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RNA, Small Interfering / metabolism
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Transcriptional Elongation Factors / genetics
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Transcriptional Elongation Factors / metabolism*
Substances
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CBX8 protein, human
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ELL protein, human
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KMT2A protein, human
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Transcriptional Elongation Factors
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Myeloid-Lymphoid Leukemia Protein
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Histone-Lysine N-Methyltransferase
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Polycomb Repressive Complex 1