Priority Research Papers:
Spatially- and temporally-controlled postnatal p53 knockdown cooperates with embryonic Schwann cell precursor Nf1 gene loss to promote malignant peripheral nerve sheath tumor formation
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Angela C. Hirbe1, Sonika Dahiya2, Dinorah Friedmann-Morvinski3, Inder M. Verma3, D. Wade Clapp4 and David H. Gutmann5
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
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
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; Nf1flox/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; Nf1flox/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.
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