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

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

Author information

1
1] Fishberg Department of Neuroscience, Friedman Brain Institute [2] Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
2
Fishberg Department of Neuroscience, Friedman Brain Institute.
3
1] Tumor Cytogenomics Laboratory, Icahn School of Medicine at Mount Sinai, New York, NY 10029 [2] Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
4
1] Fishberg Department of Neuroscience, Friedman Brain Institute [2] Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
5
1] Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 [2] Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
6
Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
7
1] Fishberg Department of Neuroscience, Friedman Brain Institute [2] Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029 [3] Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.

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.

PMID:
25683249
PMCID:
PMC4329559
DOI:
10.1038/srep08468
[Indexed for MEDLINE]
Free PMC Article

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