Abstract
The induction of the granulocytic differentiation of leukemic cells by all-trans retinoic acid (RA) has been a major breakthrough in terms of survival for acute promyelocytic leukemia (APL) patients. Here we highlight the synergism and the underlying novel mechanism between RA and the granulocyte colony-stimulating factor (G-CSF) to restore differentiation of RA-refractory APL blasts. First, we show that in RA-refractory APL cells (UF-1 cell line), PML-RA receptor alpha (RARα) is not released from target promoters in response to RA, resulting in the maintenance of chromatin repression. Consequently, RARα cannot be recruited, and the RA target genes are not activated. We then deciphered how the combination of G-CSF and RA successfully restored the activation of RA target genes to levels achieved in RA-sensitive APL cells. We demonstrate that G-CSF restores RARα recruitment to target gene promoters through the activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and the subsequent derepression of chromatin. Thus, combinatorial activation of cytokines and RARs potentiates transcriptional activity through epigenetic modifications induced by specific signaling pathways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Differentiation / drug effects*
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Cell Differentiation / genetics
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Cell Line, Tumor
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Chromatin Assembly and Disassembly / drug effects
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Enzyme Activation / drug effects
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Enzyme Induction / drug effects
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Extracellular Signal-Regulated MAP Kinases / biosynthesis*
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Gene Expression Regulation, Leukemic / drug effects
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Granulocyte Colony-Stimulating Factor / pharmacology*
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Histones / metabolism*
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Humans
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Leukemia, Promyelocytic, Acute / enzymology
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Leukemia, Promyelocytic, Acute / genetics
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Leukemia, Promyelocytic, Acute / pathology*
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MAP Kinase Signaling System / drug effects
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Mitogen-Activated Protein Kinase 3 / biosynthesis
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Mitogen-Activated Protein Kinase 6 / biosynthesis
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Phosphorylation / drug effects
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Promoter Regions, Genetic / genetics*
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Protein Binding / drug effects
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Protein Processing, Post-Translational / drug effects
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Receptors, Retinoic Acid / metabolism*
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Retinoic Acid Receptor alpha
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Transcription, Genetic / drug effects
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Tretinoin / pharmacology
Substances
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Histones
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RARA protein, human
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Receptors, Retinoic Acid
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Retinoic Acid Receptor alpha
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Granulocyte Colony-Stimulating Factor
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Tretinoin
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase 6