Neuregulin-1 overexpression and Trp53 haploinsufficiency cooperatively promote de novo malignant peripheral nerve sheath tumor pathogenesis

Malignant peripheral nerve sheath tumors (MPNSTs) are Schwann cell-derived malignancies that arise from plexiform neurofibromas in patients with mutation of the neurofibromin 1 ( NF1 ) gene. We have shown that the growth factor neuregulin-1 (NRG1) also contributes to human neurofibroma and MPNST pathogenesis and that outbred C57BL/6J × SJL/J transgenic mice overexpressing NRG1 in Schwann cells (P 0 -GGFβ3 mice) recapitulate the process of neurofibroma-MPNST progression. However, it is unclear whether NRG1 acts predominantly within NF1 -regulated signaling cascades or instead activates other essential cascades that cooperate with NF1 loss to promote tumorigenesis. We now report that tumorigenesis is suppressed in inbred P 0 -GGFβ3 mice on a C57BL/6J background. To determine whether NRG1 overexpression interacts with reduced Nf1 or Trp53 gene dosage to “unmask” tumorigenesis in these animals, we followed cohorts of inbred P 0 -GGFβ3; Nf1 +/− , P 0 -GGFβ3; Trp53 + / − and control (P 0 -GGFβ3, Nf1 +/− and Trp53 +/− ) mice for 1 year. We found no reduction in survival or tumors in control and P 0 -GGFβ3 ;Nf1 + / − mice. In contrast, P 0 -GGFβ3; Trp53 + / − mice died on average at 226 days, with MPNSTs present in 95 % of these mice. MPNSTs in inbred P 0 -GGFβ3; Trp53 + / − mice arose de novo from micro-MPNSTs that uniformly develop intraganglionically. These micro-MPNSTs are of lower grade (WHO grade II–III) than the major MPNSTs (WHO grade III–IV); array comparative genomic hybridization showed that lower grade MPNSTs also had fewer genomic abnormalities. Thus, P 0 -GGFβ3; Trp53 + / − mice represent a novel model of low- to high-grade MPNST progression. We further conclude that NRG1 promotes peripheral nervous system neoplasia predominantly via its effects on the signaling cascades affected by Nf1 loss.