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| Status |
Public on Jun 06, 2018 |
| Title |
Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively. Such combination treatment worked synergistically and caused cell cycle arrest as well as massive apoptosis. Immediate transcriptional changes from this combined MYC blockade were found using RNA-Seq profiling and showed remarkable similarities to changes in MYC target gene expression when MYCN was turned off with doxycycline in our MYCN-inducible animal model for Group 3 MB. In addition, the combination treatment significantly prolonged survival as compared to single agent therapy in orthotopically transplanted human Group 3 MB with MYC amplifications. Our data suggests that dual inhibition of CDK2 and BET bromodomains can be a novel treatment approach for suppressing MYC-driven cancer.
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| Overall design |
50 samples in total were analyzed. Four MB002 stimulated for 6h with DMSO, JQ1, Milciclib, and JQ1 and Milciclib. Five GTML2 stimulated for 6h with DMSO, JQ1, Milciclib, JQ1 and Milciclib, and doxycycline. Seven cell lines stimulated for 2h with DMSO. Two samples with human astrocytes from cerebellum and from spine. AF22 cell line. All samples in biological triplicates except doxycycline (duplicate), astrocytes and AF22 (single).
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| Contributor(s) |
Bolin S, Borgenvik A, Persson CU, Sundström A, Qi J, Bradner JE, Weiss WA, Cho Y, Weishaupt H, Swartling FJ |
| Citation(s) |
29511348 |
| Submission date |
Nov 28, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Fredrik Johansson Swartling |
| Organization name |
Uppsala University
|
| Department |
Immunology, Genetics and Pathology
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| Street address |
Dag Hammarskjölds väg 20
|
| City |
Uppsala |
| ZIP/Postal code |
752 37 |
| Country |
Sweden |
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| Platforms (2) |
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| Samples (50)
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| Relations |
| BioProject |
PRJNA420018 |
| SRA |
SRP125728 |
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