ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors

Oliver J. Mainwaring, Holger Weishaupt, Miao Zhao, Gabriela Rosén, Anna Borgenvik, Laura Breinschmid, Annemieke D. Verbaan, Stacey Richardson, Dean Thompson, Steven C. Clifford, Rebecca M. Hill, Karl Annusver, Anders Sundström, Karl O. Holmberg, Maria Kasper, Sonja Hutter and Fredrik J. Swartling ()
Additional contact information
Oliver J. Mainwaring: Uppsala University
Holger Weishaupt: Uppsala University
Miao Zhao: Uppsala University
Gabriela Rosén: Uppsala University
Anna Borgenvik: Uppsala University
Laura Breinschmid: Uppsala University
Annemieke D. Verbaan: Uppsala University
Stacey Richardson: Newcastle University Centre for Cancer
Dean Thompson: Newcastle University Centre for Cancer
Steven C. Clifford: Newcastle University Centre for Cancer
Rebecca M. Hill: Newcastle University Centre for Cancer
Karl Annusver: Karolinska Institutet
Anders Sundström: Uppsala University
Karl O. Holmberg: Uppsala University
Maria Kasper: Karolinska Institutet
Sonja Hutter: Uppsala University
Fredrik J. Swartling: Uppsala University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36847-9

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