Abstract
Alteration of lineage-specific transcriptional programs for hematopoiesis causes differentiation block and promotes leukemia development. Here, we show that AML1/ETO, the most common translocation fusion product in acute myeloid leukemia (AML), counteracts the activity of retinoic acid (RA), a transcriptional regulator of myelopoiesis. AML1/ETO participates in a protein complex with the RA receptor alpha (RARalpha) at RA regulatory regions on RARbeta2, which is a key RA target gene mediating RA activity/resistance in cells. At these sites, AML1/ETO recruits histone deacetylase, DNA methyltransferase, and DNA-methyl-CpG binding activities that promote a repressed chromatin conformation. The link among AML1/ETO, heterochromatic RARbeta2 repression, RA resistance, and myeloid differentiation block is indicated by the ability of either siRNA-AML1/ETO or the DNA methylation inhibitor 5-azacytidine to revert these epigenetic alterations and to restore RA differentiation response in AML1/ETO blasts. Finally, RARbeta2 is commonly silenced by hypermethylation in primary AML blasts but not in normal hematopoietic precursors, thus suggesting a role for the epigenetic repression of the RA signaling pathway in myeloid leukemogenesis.
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 Differentiation / genetics
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Cells, Cultured
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Core Binding Factor Alpha 2 Subunit / antagonists & inhibitors
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / metabolism
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Core Binding Factor Alpha 2 Subunit / physiology
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Gene Expression Regulation, Leukemic* / drug effects
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Gene Silencing*
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Heterochromatin / physiology*
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Humans
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Leukemia, Myeloid / genetics*
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Leukemia, Myeloid / metabolism
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Leukemia, Myeloid / pathology
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Oncogene Proteins, Fusion / antagonists & inhibitors
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Oncogene Proteins, Fusion / physiology
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Protein Binding
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RUNX1 Translocation Partner 1 Protein
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Receptors, Retinoic Acid / genetics*
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Receptors, Retinoic Acid / metabolism
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Response Elements
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Retinoid X Receptors / metabolism
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Signal Transduction / genetics
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Transfection
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Tretinoin / metabolism*
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Tretinoin / pharmacology
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U937 Cells
Substances
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AML1-ETO fusion protein, human
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Core Binding Factor Alpha 2 Subunit
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Heterochromatin
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Oncogene Proteins, Fusion
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RUNX1 Translocation Partner 1 Protein
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Receptors, Retinoic Acid
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Retinoid X Receptors
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Tretinoin