Abstract
The AML1/ETO and PML/RARalpha leukemia fusion proteins induce acute myeloid leukemia by acting as transcriptional repressors. They interact with corepressors, such as N-CoR and SMRT, that recruit a multiprotein complex containing histone deacetylases on crucial myeloid differentiation genes. This leads to gene repression contributing to generate a differentiation block. We expressed in leukemia cells containing PML/RARalpha and AML1/ETO N-CoR protein fragments derived from fusion protein/corepressor interaction surfaces. This blocks N-CoR/SMRT binding by these fusion proteins, and disrupts the repressor protein complex. In consequence, the expression of genes repressed by these fusion proteins increases and differentiation response to vitamin D3 and retinoic acid is restored in previously resistant cells. The alteration of PML/RARalpha-N-CoR/SMRT connections triggers proteasomal degradation of the fusion protein. The N-CoR fragments are biologically effective also when directly transduced by virtue of a protein transduction domain. Our data indicate that fusion protein activity is permanently required to maintain the leukemia phenotype and show the route to developing a novel therapeutic approach for leukemia, based on its molecular pathogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Cell Differentiation / drug effects
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Cell Line, Tumor
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Cholecalciferol / pharmacology
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Leukemia, Myeloid / metabolism*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / metabolism*
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Nuclear Receptor Co-Repressor 1
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Nuclear Receptor Co-Repressor 2
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Peptides / genetics
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Peptides / physiology
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Protein Structure, Tertiary / genetics
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Protein Structure, Tertiary / physiology
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RUNX1 Translocation Partner 1 Protein
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tretinoin / pharmacology
Substances
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AML1-ETO fusion protein, human
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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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NCOR2 protein, human
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Neoplasm Proteins
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Nuclear Proteins
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Nuclear Receptor Co-Repressor 1
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Nuclear Receptor Co-Repressor 2
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Oncogene Proteins, Fusion
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Peptides
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RUNX1 Translocation Partner 1 Protein
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Repressor Proteins
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Transcription Factors
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promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
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Cholecalciferol
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Tretinoin