Neuregulin‐1 overexpression and p53 haploinsufficiency cooperatively promote de novo MPNST pathogenesis

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas arising from neurofibromas in patients with neurofibromatosis type 1 (NF1). We have shown that transgenic mice expressing neuregulin‐1 (NRG1) in Schwann cells (P0‐ GGFβ3 mice) develop neurofibromas and MPNSTs on a C57BL/6 × SJL background. However, on a C57BL/6J background, P0GGFβ3 mice fail to develop tumors despite persistent transgene expression and Schwann cell hyperplasia. Hypothesizing that tumor suppressor gene loss would complement NRG1 overexpression and rescue tumorigenesis, we created cohorts of P0GGFβ3 >;Nf1+/−, P0GGFβ3; Trp53+/− and control (P0‐GGFβ3, Nf1+/−, Trp53+/−) mice and compared their survival and tumorigenesis. The survival of P0GGFβ3; Nf1+/− mice was equivalent to controls and they did not develop tumors. In contrast, P0GGFβ3; Trp53+/− mice died earlier (mean survival, 232 days) and MPNSTs were present in 88.4% of these mice. Further, unlike outbred P0GGFβ3 mice, MPNSTs in P0GGFβ3; Trp53+/− mice arose de novo rather than from neurofibromas. Real‐time PCR, immunohistochemical and sequence analyses showed persistent wild‐type p53 expression. These findings show that NRG1 acts in the same pathways affected by Nf1 loss and suggest that Trp53 haploinsufficiency in the face of NRG1‐driven Schwann cell hyperplasia destabilizes the genome and promotes de novo MPNST tumorigenesis. Funded by NIH and DOD.