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- Title
ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors.
- Authors
Mainwaring, Oliver J.; Weishaupt, Holger; Zhao, Miao; Rosén, Gabriela; Borgenvik, Anna; Breinschmid, Laura; Verbaan, Annemieke D.; Richardson, Stacey; Thompson, Dean; Clifford, Steven C.; Hill, Rebecca M.; Annusver, Karl; Sundström, Anders; Holmberg, Karl O.; Kasper, Maria; Hutter, Sonja; Swartling, Fredrik J.
- Abstract
Medulloblastoma, the most common malignant pediatric brain tumor, often harbors MYC amplifications. Compared to high-grade gliomas, MYC-amplified medulloblastomas often show increased photoreceptor activity and arise in the presence of a functional ARF/p53 suppressor pathway. Here, we generate an immunocompetent transgenic mouse model with regulatable MYC that develop clonal tumors that molecularly resemble photoreceptor-positive Group 3 medulloblastoma. Compared to MYCN-expressing brain tumors driven from the same promoter, pronounced ARF silencing is present in our MYC-expressing model and in human medulloblastoma. While partial Arf suppression causes increased malignancy in MYCN-expressing tumors, complete Arf depletion promotes photoreceptor-negative high-grade glioma formation. Computational models and clinical data further identify drugs targeting MYC-driven tumors with a suppressed but functional ARF pathway. We show that the HSP90 inhibitor, Onalespib, significantly targets MYC-driven but not MYCN-driven tumors in an ARF-dependent manner. The treatment increases cell death in synergy with cisplatin and demonstrates potential for targeting MYC-driven medulloblastoma. CDKN2A loss and p53 mutations are rare in MYC-driven Group 3 medulloblastomas (MBs). Here the authors generated a transgenic mouse model of Group 3 MB by MYC overexpression and show that MYC suppresses ARF to drive tumorigenesis.
- Subjects
BRAIN tumors; CISPLATIN; TRANSGENIC mice; LABORATORY mice; MEDULLOBLASTOMA; CELL death
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-36847-9