Abstract
Retinoic acids (RA) play a key role in myeloid differentiation through their agonistic nuclear receptors (RAR alpha/RXR) to modulate the expression of target genes. In acute promyelocytic leukemia (APL) cells with rearrangement of retinoic acid receptor a (RAR alpha) (including: PML-RAR alpha, PLZF-RAR alpha, NPM-RAR alpha, NuMA- RAR alpha or STAT5b-RAR alpha) as a result of chromosomal translocations, the RA signal pathway is disrupted and myeloid differentiation is arrested at the promyelocytic stage. Pharmacologic dosage of all-trans retinoic acid (ATRA) directly modulates PML-RAR alpha and its interaction with the nuclear receptor co-repressor complex, which restores the wild-type RAR alpha/RXR regulatory pathway and induces the transcriptional expression of downstream genes. Analysing gene expression profiles in APL cells before and after ATRA treatment represents a useful approach to identify genes whose functions are involved in this new cancer treatment. A chronologically well coordinated modulation of ATRA-regulated genes has thus been revealed which seems to constitute a balanced functional network underlying decreased cellular proliferation, initiation and progression of maturation, and maintenance of cell survival before terminal differentiation.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Cell Differentiation / drug effects*
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Gene Expression Regulation, Leukemic / drug effects*
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HL-60 Cells / cytology
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HL-60 Cells / drug effects
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Humans
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Leukemia, Promyelocytic, Acute / drug therapy
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Leukemia, Promyelocytic, Acute / genetics
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Leukemia, Promyelocytic, Acute / pathology*
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Neoplasm Proteins / drug effects*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Nuclear Proteins / physiology
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Nuclear Receptor Co-Repressor 1
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Oncogene Proteins, Fusion / drug effects*
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Oncogene Proteins, Fusion / genetics
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Receptors, Retinoic Acid / agonists*
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / physiology
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Repressor Proteins / physiology
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Retinoic Acid Receptor alpha
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Retinoid X Receptors
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Signal Transduction / drug effects
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Transcription Factors / physiology
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Transcription, Genetic / drug effects
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Translocation, Genetic
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Tretinoin / pharmacology*
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Tretinoin / therapeutic use
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Tumor Cells, Cultured / cytology
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Tumor Cells, Cultured / drug effects
Substances
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Antineoplastic Agents
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NCOR1 protein, human
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NPM-RARalpha protein, human
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Neoplasm Proteins
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NuMa-RARalpha protein, human
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Nuclear Proteins
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Nuclear Receptor Co-Repressor 1
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Oncogene Proteins, Fusion
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PLZF-RARalpha fusion protein, human
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RARA protein, human
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Receptors, Retinoic Acid
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Repressor Proteins
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Retinoic Acid Receptor alpha
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Retinoid X Receptors
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Transcription Factors
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promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
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Tretinoin