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| Status |
Public on Dec 21, 2022 |
| Title |
ARF suppression by MYC but not MYCN confers increased malignancy of Group 3 medulloblastoma |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Group 3 medulloblastoma (MB) carries the worst prognosis of the four molecular subgroups of MB. MYC amplifications represent the most common genetic alteration in Group 3 MB. By specifically driving MYC in hindbrain cells using a Tet-OFF system, we established a novel murine model of MB (GMYC) that accurately recapitulates human Group 3 MB. GMYC tumours develop with 60-70% penetrance, without p53 mutations, and are monoclonal as revealed by multicolour cell fate tracing. Compared to MYCN-driven Group 3 tumours driven from the same promoter, the ARF suppressor gene was significantly downregulated in GMYC tumours and specifically silenced by methylation in MYC-amplified human MB. While MYCN-driven tumour malignancy was more sensitive to ARF depletion, it dramatically increased the metastatic spread of MYC-driven tumours. Finally, the DNMT inhibitor decitabine could restore ARF levels and suppress MYC-driven tumour growth providing a promising targeting approach for these high-risk tumours.
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| Overall design |
Total of 14 tumor biopsies were profiled for RNA expression; six from GMYC model and eight from GTML model. In addition, two GMYC Arf knock-out cell lines, four GTML Arf k-o cell lines, three GMYC cell lines treated with Onalespib, three GMYC cell lines treated with DMSO, three GTML2 cell lines treated with Onalespib and three GTML2 cell lines with DMSO were also sequenced.
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| Contributor(s) |
Mainwaring O, Weishaupt H, Hutter S, Rosén G, Breinschmid L, Sundström A, Annusver K, Kasper M, Swartling F |
| Citation(s) |
36869047 |
| |
| Submission date |
Oct 22, 2019 |
| Last update date |
Mar 22, 2023 |
| 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) |
| GPL16331 |
Ion Torrent PGM (Mus musculus) |
| GPL27583 |
Ion Torrent S5 XL (Mus musculus) |
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| Samples (32)
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| Relations |
| BioProject |
PRJNA578864 |
| SRA |
SRP226589 |
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