Spatially- and temporally-controlled postnatal p53 knockdown cooperates with embryonic Schwann cell precursor Nf1 gene loss to promote malignant peripheral nerve sheath tumor formation

// Angela C. Hirbe 1 , Sonika Dahiya 2 , Dinorah Friedmann-Morvinski 3 , Inder M. Verma 3 , D. Wade Clapp 4 and David H. Gutmann 5 1 Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA 2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA 3 The Salk Institute of Biological Studies, Laboratory of Genetics, La Jolla, CA, USA 4 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA 5 Department of Neurology, Washington University, St. Louis, MO, USA Correspondence to: David H. Gutmann, email: // Keywords : Neurofibromatosis Type 1, MPNST, lentivirus, p53, mouse models Received : October 26, 2015 Accepted : January 27, 2016 Published : February 07, 2016 Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas that arise sporadically or in association with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. In individuals with NF1, MPNSTs are hypothesized to arise from Nf1 -deficient Schwann cell precursor cells following the somatic acquisition of secondary cooperating genetic mutations ( e.g ., p53 loss). To model this sequential genetic cooperativity, we coupled somatic lentivirus-mediated p53 knockdown in the adult right sciatic nerve with embryonic Schwann cell precursor Nf1 gene inactivation in two different Nf1 conditional knockout mouse strains. Using this approach, ~60% of mice with Periostin-Cre-mediated Nf1 gene inactivation (Periostin-Cre; Nf1 flox/flox mice) developed tumors classified as low-grade MPNSTs following p53 knockdown (mean, 6 months). Similarly, ~70% of Nf1 +/- mice with GFAP-Cre-mediated Nf1 gene inactivation (GFAP-Cre; Nf1 flox/null mice) developed low-grade MPNSTs following p53 knockdown (mean, 3 months). In addition, wild-type and Nf1+/- mice with GFAP-Cre-mediated Nf1 loss develop MPNSTs following somatic p53 knockout with different latencies, suggesting potential influences of Nf1+/- stromal cells in MPNST pathogenesis. Collectively, this new MPNST model system permits the analysis of somatically-acquired events as well as tumor microenvironment signals that potentially cooperate with Nf1 loss in the development and progression of this deadly malignancy.