title: Double minute amplification of mutant PDGF receptor α in a mouse glioma model.
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.
authors: 1] Fishberg Department of Neuroscience, Friedman Brain Institute [2] Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors: Hongyan
authors: H
authors: Zou
authors: Fishberg Department of Neuroscience, Friedman Brain Institute.
authors: Rui
authors: R
authors: Feng
authors: Fishberg Department of Neuroscience, Friedman Brain Institute.
authors: Yong
authors: Y
authors: Huang
authors: 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.
authors: Joseph
authors: J
authors: Tripodi
authors: 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.
authors: Vesna
authors: V
authors: Najfeld
authors: 1] Fishberg Department of Neuroscience, Friedman Brain Institute [2] Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors: Nadejda M
authors: NM
authors: Tsankova
authors: 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.
authors: Maryam
authors: M
authors: Jahanshahi
authors: Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors: Lorin E
authors: LE
authors: Olson
authors: 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.
authors: Philippe
authors: P
authors: Soriano
authors: 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.
authors: Roland H
authors: RH
authors: Friedel
mesh_terms: D051701:Activating Transcription Factor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000662:veterinary; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004270:DNA, Circular / Q000737:chemistry; D004195:Disease Models, Animal; D005784:Gene Amplification; D055879:Gene Knock-In Techniques; D005910:Glioma / Q000378:metabolism / Q000473:pathology* / Q000662:veterinary; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D017354:Point Mutation; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: C081452:Atf4 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004270:DNA, Circular; D051701:Activating Transcription Factor 4; D020796:Receptor, Platelet-Derived Growth Factor alpha