Journal
ONCOTARGET
Volume 7, Issue 7, Pages 7403-7414Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7232
Keywords
Neurofibromatosis Type 1; MPNST; lentivirus; p53; mouse models
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Funding
- Schnuck Markets Inc.
- St. Louis Men's Group Against Cancer
- Neuroscience Blueprint Core grant NIH [P30 NS057105]
- [T32 HL007088]
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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, similar to 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, similar to 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.
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