Double minute amplification of mutant PDGF receptor α in a mouse glioma model

Sci Rep. 2015 Feb 16;5:8468. doi: 10.1038/srep08468.

Abstract

In primary brain tumors, oncogenes are frequently amplified and maintained on extrachromosomal DNA as double minutes (DM), but the underlying mechanisms remain poorly understood. We have generated a mouse model of malignant glioma based on knock-in of a mutant PDGF receptor α (PDGFRα) that is expressed in oligodendrocyte precursor cells (OPCs) after activation by a Cre recombinase. In the tumor suppressor INK4/Arf(-/-) background, mutant animals frequently developed brain tumors resembling anaplastic human gliomas (WHO grade III). Besides brain tumors, most animals also developed aggressive fibrosarcomas, likely triggered by Cre activation of mutant PDGFRα in fibroblastic cell lineages. Importantly, in the brain tumors and cell lines derived from brain tumor tissues, we identified a high prevalence of DM Pdgfra gene amplification, suggesting its occurrence as an early mutational event contributing to the malignant transformation of OPCs. Amplicons extended beyond the Pdgfra locus and included in some cases neighboring genes Kit and Kdr. Our genetically defined mouse brain tumor model therefore supports OPC as a cell of origin for malignant glioma and offers an example of a defined temporal sequence of mutational events, thus providing an entry point for a mechanistic understanding of DM gene amplification and its functionality in gliomagenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / deficiency
  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Alleles
  • Animals
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Brain Neoplasms / veterinary
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA, Circular / chemistry
  • Disease Models, Animal
  • Gene Amplification*
  • Gene Knock-In Techniques
  • Glioma / metabolism
  • Glioma / pathology*
  • Glioma / veterinary
  • In Situ Hybridization, Fluorescence
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Inbred C57BL
  • Oligodendroglia / cytology
  • Oligodendroglia / metabolism
  • Point Mutation
  • Receptor, Platelet-Derived Growth Factor alpha / genetics*
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Severity of Illness Index

Substances

  • Atf4 protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA, Circular
  • Activating Transcription Factor 4
  • Receptor, Platelet-Derived Growth Factor alpha