| Transgenic Mice Overexpressing Neuregulin-1 Model Neurofibroma-Malignant Peripheral Nerve Sheath Tumor Progression and Implicate Specific Chromosomal Copy Number Variations in Tumorigenesis. | |
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MedLine Citation:
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PMID: 23321323 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Patients with neurofibromatosis type 1 (NF1) develop benign plexiform neurofibromas that frequently progress to become malignant peripheral nerve sheath tumors (MPNSTs). A genetically engineered mouse model that accurately models plexiform neurofibroma-MPNST progression in humans would facilitate identification of somatic mutations driving this process. We previously reported that transgenic mice overexpressing the growth factor neuregulin-1 in Schwann cells (P(0)-GGFβ3 mice) develop MPNSTs. To determine whether P(0)-GGFβ3 mice accurately model human neurofibroma-MPNST progression, cohorts of these animals were monitored through death and were necropsied; 94% developed multiple neurofibromas, with 70% carrying smaller numbers of MPNSTs. Nascent MPNSTs were identified within neurofibromas, suggesting that these sarcomas arise from neurofibromas. Although neurofibromin expression was maintained, P(0)-GGFβ3 MPNSTs exhibited Ras hyperactivation, as in human NF1-associated MPNSTs. P(0)-GGFβ3 MPNSTs also exhibited abnormalities in the p16(INK4A)-cyclin D/CDK4-Rb and p19(ARF)-Mdm-p53 pathways, analogous to their human counterparts. Array comparative genomic hybridization (CGH) demonstrated reproducible chromosomal alterations in P(0)-GGFβ3 MPNST cells (including universal chromosome 11 gains) and focal gains and losses affecting 39 neoplasia-associated genes (including Pten, Tpd52, Myc, Gli1, Xiap, and Bbc3/PUMA). Array comparative genomic hybridization also identified recurrent focal copy number variations affecting genes not previously linked to neurofibroma or MPNST pathogenesis. We conclude that P(0)-GGFβ3 mice represent a robust model of neurofibroma-MPNST progression useful for identifying novel genes driving neurofibroma and MPNST pathogenesis. |
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Authors:
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Syed J Kazmi; Stephanie J Byer; Jenell M Eckert; Amy N Turk; Richard P H Huijbregts; Nicole M Brossier; William E Grizzle; Fady M Mikhail; Kevin A Roth; Steven L Carroll |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-12 |
Journal Detail:
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Title: The American journal of pathology Volume: - ISSN: 1525-2191 ISO Abbreviation: Am. J. Pathol. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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