Abstract
Acute promyelocytic leukemia (APL) is characterized by an arrest of granulocytic differentiation and a reciprocal t(15;17) translocation fusing the PML gene to the retinoic acid receptor alpha (RAR alpha) gene. PML was recently identified as a potential transcription factor. In non hematopoietic cells, the transfected PML-RAR alpha product binds all trans retinoic acid and exhibits altered transactivating properties when compared with RAR alpha. A major question raised by these observations is whether PML-RAR alpha contributes to the inhibition of myeloid differentiation. We find that in myeloid cell lines responsive to retinoic acid, PML-RAR alpha blocks retinoic acid mediated transactivation and totally abrogates the retinoic acid mediated granulocytic differentiation. These findings strongly suggest that PML-RAR alpha may, by blocking normal retinoic acid dependent myeloid differentiation, participate in the leukemogenesis of APL. The fact that high doses of all-trans retinoic acid relieve the inhibitory effect of PML-RAR alpha corroborates the therapeutic effect of all-trans retinoic acid in APL patients.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Base Sequence
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Bone Marrow / chemistry
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Bone Marrow / ultrastructure
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Bone Marrow Cells*
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Cell Differentiation / drug effects
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Cell Line
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Cholecalciferol / pharmacology
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Chromosomes, Human, Pair 15*
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Chromosomes, Human, Pair 17*
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DNA, Neoplasm / genetics
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Dose-Response Relationship, Drug
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Granulocytes / cytology*
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Humans
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Leukemia, Promyelocytic, Acute / genetics
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Molecular Sequence Data
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Neoplasm Proteins*
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Nuclear Proteins*
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Promyelocytic Leukemia Protein
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Receptors, Retinoic Acid / analysis
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / physiology*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / physiology*
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Retinoic Acid Receptor alpha
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transcriptional Activation / genetics*
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Transfection
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Translocation, Genetic / genetics*
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Tretinoin / pharmacology*
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Tumor Cells, Cultured
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Tumor Suppressor Proteins
Substances
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DNA, Neoplasm
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Neoplasm Proteins
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Nuclear Proteins
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Promyelocytic Leukemia Protein
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RARA protein, human
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Receptors, Retinoic Acid
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Recombinant Fusion Proteins
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Retinoic Acid Receptor alpha
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Transcription Factors
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Tumor Suppressor Proteins
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PML protein, human
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Cholecalciferol
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Tretinoin