Oncotarget: p53 knockdown to promote malignant peripheral nerve sheath tumor formation скачать в хорошем качестве

Oncotarget: p53 knockdown to promote malignant peripheral nerve sheath tumor formation

Oncotarget published "Spatially- and temporally-controlled postnatal p53 knockdown cooperates with embryonic Schwann cell precursor Nf1 gene loss to promote malignant peripheral nerve sheath tumor formation" which reported that 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. ORIGINAL SOURCE - https://www.oncotarget.com/news/pr/p5... Using this approach, ~60% of mice with Periostin-Cre-mediated Nf1 gene inactivation developed tumors classified as low-grade MPNSTs following p53 knockdown. Similarly, ~70% of Nf1 /- mice with GFAP-Cre-mediated Nf1 gene inactivation developed low-grade MPNSTs following p53 knockdown. 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, presented in this Oncotarget study, 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. Dr. David H. Gutmann from Washington University said, "MPNSTs are an aggressive subtype of soft-tissue sarcoma that develops in association with peripheral nerves or nerve roots." Individuals with NF1 are born with a germline mutation in one copy of the NF1 gene, such that all cells in their bodies have one dysfunctional NF1 allele. Consistent with a key role for the NF1 gene in both NF1-associated and sporadic MNPST pathogenesis, bi-allelic NF1 gene inactivation has been reported in approximately 60-90% of NF1-associated MPNSTs and 40-60% of sporadic cases. In this regard, genetically-engineered mouse lines with conditional Nf1 gene inactivation in Schwann cell precursors do not develop MPNSTs unless coupled with concomitant Trp53 loss, epidermal growth factor receptor amplification, Pten loss, or Ink4a deletion. To generate a model in which temporal control of the transforming genetic alteration can be achieved in a single nerve location, we employed two GEM strains in which Cre-mediated Nf1 inactivation occurs in Schwann cell precursor cells during embryogenesis and p53 knockdown is somatically acquired at 6-8 weeks of age in cells within the right sciatic nerve. The coupling of somatic retroviral knockdown and embryonic Nf1 gene inactivation establishes an experimentally-manipulable platform to evaluate other cooperating genetic changes in MPNST pathogenesis as well as preclinical mouse strains in which clinical symptomatology can be used to monitor tumor progression. The Gutmann Research Team concluded in their Oncotarget Priority Research Paper, "the implementation of this experimental MPNST model system has allowed us to make two important observations. First, we demonstrate that somatic reduction, but not absence, of Trp53 expression following Nf1 gene inactivation is sufficient for MPNST formation. Second, we demonstrate that MPNST formation can occur in the absence of a microenvironment composed of cells heterozygous for a germline Nf1 gene mutation. Future studies employing this platform may facilitate more rapid analyses of the contributions of other cooperating events to MPNST pathogenesis, the role of the tumor microenvironment in MPNST growth, and the development of radiologic and molecular biomarkers of malignant transformation." DOI - https://doi.org/10.18632/oncotarget.7232 Full text - https://www.oncotarget.com/article/72... Correspondence to - David H. Gutmann - [email protected] Keywords - Neurofibromatosis Type 1, MPNST, lentivirus, p53, mouse models About Oncotarget Oncotarget is a biweekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud -   / oncotarget   Facebook -   / oncotarget   Twitter -   / oncotarget   LinkedIn -   / oncotarget   Pinterest -   / oncotarget   Reddit -   / oncotarget   Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact [email protected] 18009220957x105