title: Spatially- and temporally-controlled postnatal p53 knockdown cooperates with embryonic Schwann cell precursor Nf1 gene loss to promote malignant peripheral nerve sheath tumor formation.
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.
authors: Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors: Angela C
authors: AC
authors: Hirbe
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Sonika
authors: S
authors: Dahiya
authors: The Salk Institute of Biological Studies, Laboratory of Genetics, La Jolla, CA, USA.
authors: Dinorah
authors: D
authors: Friedmann-Morvinski
authors: The Salk Institute of Biological Studies, Laboratory of Genetics, La Jolla, CA, USA.
authors: Inder M
authors: IM
authors: Verma
authors: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: D Wade
authors: DW
authors: Clapp
authors: Department of Neurology, Washington University, St. Louis, MO, USA.
authors: David H
authors: DH
authors: Gutmann
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009442:Neurilemmoma / Q000235:genetics / Q000473:pathology*; D025542:Neurofibromin 1 / Q000502:physiology*; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology*; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D025542:Neurofibromin 1; D016159:Tumor Suppressor Protein p53
keywords: MPNST; Neurofibromatosis type 1; lentivirus; mouse models; p53