Abstract
We determined the effects of severe hypoxia (∼0.1% O2) on acute myeloid leukemia cells expressing the AML1/ETO oncogene. Incubation of Kasumi-1 cells in hypoxia induced growth arrest, apoptosis and reduction of AML1/ETO protein expression. The conditional expression of AML1/ETO in U937-A/E cells showed that hypoxia induces marked apoptosis in AML1/ETO-expressing cells only, pointing to AML1/ETO as a factor predisposing cells to hypoxia-induced apoptosis. In AML1/ETO-expressing cells, hypoxia enhanced TRAIL expression and its proapoptotic effects. AML1/ETO was found to bind TRAIL promoter and induce TRAIL transcription, although TRAIL expression was restrained by a concomitant relative transcription block. In hypoxia, such a TRAIL repression was removed and an increase of TRAIL expression was induced. Finally, blocking anti-TRAIL antibodies markedly reduced (Kasumi-1 cells) or completely inhibited (U937-A/E cells) hypoxia-induced apoptosis. Taken together, these results indicated that hypoxia induces apoptosis in AML1/ETO-expressing cells via a TRAIL/caspase 8-dependent autocrine loop and that TRAIL is a key regulator of hypoxia-induced apoptosis in these cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies / pharmacology
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Apoptosis / drug effects
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Base Sequence
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Caspase 8 / genetics
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Caspase 8 / metabolism
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Cell Cycle Checkpoints / drug effects
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Cell Hypoxia / genetics*
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Cell Line, Tumor
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Core Binding Factor Alpha 2 Subunit / genetics*
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Core Binding Factor Alpha 2 Subunit / metabolism
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Gene Expression Regulation, Leukemic / drug effects*
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Humans
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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Molecular Sequence Data
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Oxygen / pharmacology
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Promoter Regions, Genetic
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Protein Binding
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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RUNX1 Translocation Partner 1 Protein
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Signal Transduction / drug effects
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TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors
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TNF-Related Apoptosis-Inducing Ligand / genetics*
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TNF-Related Apoptosis-Inducing Ligand / metabolism
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transcription, Genetic / drug effects
Substances
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Antibodies
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Core Binding Factor Alpha 2 Subunit
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Proto-Oncogene Proteins
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RUNX1 Translocation Partner 1 Protein
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RUNX1 protein, human
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RUNX1T1 protein, human
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Transcription Factors
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Caspase 8
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Oxygen