Document Detail


Transgenic mice overexpressing neuregulin-1 model neurofibroma-malignant peripheral nerve sheath tumor progression and implicate specific chromosomal copy number variations in tumorigenesis.
MedLine Citation:
PMID:  23321323     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
Related Documents :
24166123 - Recombination around the tm2a and mi resistance genes in different crosses of lycopersi...
23066103 - Telomere length homeostasis and telomere position effect on a linear human artificial c...
9830013 - Steroid-selective initiation of chromatin remodeling and transcriptional activation of ...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-01-13
Journal Detail:
Title:  The American journal of pathology     Volume:  182     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-26     Completed Date:  2013-08-08     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  646-67     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Base Pairing / genetics
Cell Cycle
Cell Transformation, Neoplastic / genetics*,  pathology
Chromosomes, Mammalian / genetics*
Comparative Genomic Hybridization
DNA Copy Number Variations / genetics*
Disease Models, Animal
Disease Progression*
Humans
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nerve Sheath Neoplasms / genetics,  pathology*
Neuregulin-1 / metabolism*
Neurofibroma / genetics,  pathology*
Neurofibromin 1 / metabolism
Peripheral Nervous System / metabolism,  pathology
Signal Transduction / genetics
Tumor Markers, Biological / metabolism
ras Proteins / metabolism
Grant Support
ID/Acronym/Agency:
F30 NS063626/NS/NINDS NIH HHS; P30 CA013148/CA/NCI NIH HHS; P30 NS057098/NS/NINDS NIH HHS; P30 NS474466/NS/NINDS NIH HHS; R01 CA122804/CA/NCI NIH HHS; R01 CA134773/CA/NCI NIH HHS; R01 NS048353/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Neuregulin-1; 0/Neurofibromin 1; 0/Tumor Markers, Biological; EC 3.6.5.2/ras Proteins
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Alterations in glucose homeostasis in a murine model of Chagas disease.
Next Document:  Mesenchymal stromal cells: misconceptions and evolving concepts.