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

Lookup NU author(s): Dr Stacey Richardson, Dean Thompson, Professor Steven CliffordORCiD, Dr Rebecca Hill

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2023. The Author(s).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.

Publication metadata

Author(s): Mainwaring OJ, Weishaupt H, Zhao M, Rosen G, Borgenvik A, Breinschmid L, Verbaan AD, Richardson S, Thompson D, Clifford SC, Hill RM, Annusver K, Sundstrom A, Holmberg KO, Kasper M, Hutter S, Swartling FJ

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2023

Volume: 14

Issue: 1

Online publication date: 03/03/2023

Acceptance date: 20/02/2023

Date deposited: 20/03/2023

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41467-023-36847-9

DOI: 10.1038/s41467-023-36847-9

PubMed id: 36869047

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