|
| Status |
Public on Jan 12, 2018 |
| Title |
Targeted inhibition of TET1 transcription as a potent therapeutic strategy for acute myeloid leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by high throughput sequencing
|
| Summary |
Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a potent oncogene 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 level 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, an optimized derivative of NSC-370284, exhibited an even more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three folds. NSC-370284 and its derivative showed strong synergistic effects with standard chemotherapy. NSC-370284 directly targeted STAT3/5, transcriptional activators of TET1, and thus repressed TET1 expression. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.
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| |
|
| Overall design |
Selective 5hmC chemical labeling approach to profile genome-wide 5hmC distributions across different samples
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| |
|
| Contributor(s) |
Jiang X, Nie J, Cui X, He C, Chen J |
| Citation(s) |
29235481 |
| |
| Submission date |
Apr 05, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Xiaolong Cui |
| E-mail(s) |
xiaolong.cui@northwestern.edu
|
| Organization name |
Northwestern University
|
| Department |
Department of Preventive Medicine
|
| Street address |
680 N Lake Shore Drive
|
| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60611 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
|
| Samples (7)
|
|
| Relations |
| BioProject |
PRJNA381698 |
| SRA |
SRP103071 |
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