Abstract
Although retinoic acid receptor alpha (RARalpha) agonists induce the maturation of t(15;17) acute promyelocytic leukemia (APL) cells, drug treatment also selects leukemic blasts expressing PML-RARalpha fusion proteins with mutated ligand-binding domains that no longer respond to all-trans retinoic acid (ATRA). Here we report a novel RARalpha-independent signaling pathway that induces maturation of both ATRA-sensitive and ATRA-resistant APL NB4 cells, and does not invoke the ligand-induced alteration of PML-RARalpha signaling, stability or compartmentalization. This response involves a cross-talk between RXR agonists and protein kinase A signaling. Our results indicate the existence of a separate RXR-dependent maturation pathway that can be activated in the absence of known ligands for RXR heterodimerization partners.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Base Sequence
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Benzoates / pharmacology
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Blast Crisis
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Chromosomes, Human, Pair 15*
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Chromosomes, Human, Pair 17*
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Dimerization
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Humans
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Leukemia, Promyelocytic, Acute / genetics*
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Leukemia, Promyelocytic, Acute / pathology*
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Leukemia, Promyelocytic, Acute / physiopathology
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / physiology
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / physiology
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Receptor Cross-Talk
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Receptors, Retinoic Acid / drug effects
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Receptors, Retinoic Acid / physiology*
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / metabolism
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Retinoic Acid Receptor alpha
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Retinoid X Receptors
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Retinoids / pharmacology
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Signal Transduction*
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Transcription Factors / physiology*
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Translocation, Genetic*
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Tretinoin / pharmacology
Substances
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Benzoates
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Neoplasm Proteins
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Oncogene Proteins, Fusion
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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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Retinoid X Receptors
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Retinoids
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Transcription Factors
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promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
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retinoic acid receptor beta
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SR 11237
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Tretinoin
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Cyclic AMP-Dependent Protein Kinases