Abstract
The variant acute promyelocytic leukemia (APL) translocation t(5;17)(q35;q21) fuses the N-terminus of nucleophosmin (NPM1) to the retinoic acid receptor alpha (RARA). We found that ectopic NPM1-RARA expression decreased TP53 protein levels in target cells. NPM1-RARA impaired TP53-dependent transcription. Cells expressing NPM1-RARA were more resistant to apoptotic stimuli. This work identifies the TP53 tumor suppressor as a novel target through which NPM1-RARA impacts leukemogenesis, and confirms the importance of impairment of TP53 in establishment of the APL phenotype.
Keywords:
Acute promyelocytic leukemia; NPM1-RARA; TP53; apoptosis; nucleophosmin.
MeSH terms
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Animals
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Apoptosis
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COS Cells
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Carcinogenesis / genetics
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Carcinogenesis / metabolism
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Chlorocebus aethiops
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Chromosomes, Human, Pair 17 / genetics
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Chromosomes, Human, Pair 5 / genetics
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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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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Nucleophosmin
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Retinoic Acid Receptor alpha / genetics
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Retinoic Acid Receptor alpha / metabolism*
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Translocation, Genetic
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Tumor Suppressor Protein p53 / metabolism*
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U937 Cells
Substances
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NPM1 protein, human
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Nuclear Proteins
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Oncogene Proteins, Fusion
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RARA protein, human
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Retinoic Acid Receptor alpha
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TP53 protein, human
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Tumor Suppressor Protein p53
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Nucleophosmin