|
| Status |
Public on Sep 06, 2022 |
| Title |
Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma [CUT&RUN, 2] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic PAX3–FOXO1 fusion protein, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability for PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth by disrupting the expression of CRC TFs caused by epigenetic alterations of PAX3–FOXO1-governed super enhancers. Combining KDM4B inhibition with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable mechanism required for maintenance of PAX3-FOXO1-related CRC TF network, which may translate to a novel therapeutic approach for fusion-positive RMS.
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| |
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| Overall design |
Examination of chromatin changes with QC6352 treatment by CUT&RUN
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| |
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| Contributor(s) |
Lily M, Ying S, Fang J, Jin H, Yang J |
| Citation(s) |
35857643 |
| |
| Submission date |
Mar 16, 2022 |
| Last update date |
Sep 07, 2022 |
| Contact name |
Hongjian Jin |
| E-mail(s) |
hongjian.jin@STJUDE.ORG
|
| Organization name |
St Jude Children's Research Hospital
|
| Department |
Center for Applied Bioinformatics
|
| Street address |
262 Danny Thomas Place
|
| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38015 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (18)
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| This SubSeries is part of SuperSeries: |
| GSE157095 |
Targeting KDM4B to disrupt the core regulatory transcription network governed by PAX3-FOXO1 in high-risk rhabdomyosarcoma |
|
| Relations |
| BioProject |
PRJNA816825 |
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