Transgenic mice overexpressing neuregulin-1 model neurofibroma-malignant peripheral nerve sheath tumor progression and implicate specific chromosomal copy number variations in tumorigenesis.

Abstract

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
• Journal: The American journal of pathology (Am J Pathol) Vol. 182 Issue 3 Pg. 646-67 (Mar 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23321323 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Neuregulin-1
• Neurofibromin 1
• ras Proteins

Topics

• Animals
• Base Pairing (genetics)
• Biomarkers, Tumor (metabolism)
• 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)
• ras Proteins (metabolism)