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

Nat Commun. 2023 Mar 3;14(1):1221. doi: 10.1038/s41467-023-36847-9.


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 types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms*
  • Cerebellar Neoplasms*
  • Child
  • Glioma*
  • Humans
  • Medulloblastoma*
  • Mice
  • Mice, Transgenic
  • N-Myc Proto-Oncogene Protein
  • Proto-Oncogene Proteins c-myc*


  • N-Myc Proto-Oncogene Protein
  • Proto-Oncogene Proteins c-myc