Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29235481.
- Also identified by DOI 10.1038/s41467-017-02290-w and PMC identifier 5727390.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Enzyme Inhibitors
- Leukemia, Myeloid, Acute
- Mixed Function Oxygenases
- Proto-Oncogene Proteins
- STAT3 Transcription Factor
- STAT5 Transcription Factor