Abstract
Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML. NSC-311068 and especially NSC-370284 significantly repressed TET1-high AML progression in vivo. UC-514321, a structural analog of NSC-370284, exhibited a more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three fold. NSC-370284 and UC-514321 both directly target STAT3/5, transcriptional activators of TET1, and thus repress TET1 expression. They also exhibit strong synergistic effects with standard chemotherapy. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Cell Line, Tumor
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Daunorubicin / administration & dosage
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacology*
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Gene Expression Regulation, Leukemic / drug effects
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Humans
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Kaplan-Meier Estimate
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Leukemia, Experimental / drug therapy
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Leukemia, Experimental / genetics
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Leukemia, Experimental / metabolism
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism
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Mice, Inbred C57BL
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Mixed Function Oxygenases / antagonists & inhibitors*
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Mixed Function Oxygenases / genetics
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Mixed Function Oxygenases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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RNA Interference
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STAT3 Transcription Factor / antagonists & inhibitors*
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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STAT5 Transcription Factor / antagonists & inhibitors*
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / metabolism
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THP-1 Cells
Substances
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Enzyme Inhibitors
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Proto-Oncogene Proteins
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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Mixed Function Oxygenases
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TET1 protein, human
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Daunorubicin