Transgenic Mice Overexpressing Neuregulin-1 Model Neurofibroma-Malignant Peripheral Nerve Sheath Tumor Progression and Implicate Specific Chromosomal Copy Number Variations in Tumorigenesis

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-GGF beta 3 mice) develop MPNSTs. To determine whether P-0-GGF beta 3 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-GGF beta 3 MPNSTs exhibited Ras hyperactivation, as in human NF1-associated MPNSTs. P-0-GGF beta 3 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-GGF beta 3 MPNST cells (including universal chromosome 11 gains) and focal gains and losses affecting 39 neoplasia-associated genes (including Pten, Tpd52, Myc, Gil1, 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-GGF beta 3 mice represent a robust model of neurofibroma-MPNST progression useful for identifying novel genes driving neurofibroma and MPNST pathogenesis. (Am J Pathol 2013, 182: 646-667; http://dx.doi.org/10.1016/j.ajpath.2012.11.017)