Abstract It is hypothesized that many genetic changes are required for the transformation process of sporadic malignant peripheral nerve sheath tumor (MPNST). Currently, Schwann cells and/or their precursor cells are believed to be the primary pathogenic cell source in peripheral nerve sheath tumor (PNST) formation and malignant progression. Recently, it has been shown that phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) both play important roles in the initiation of peripheral nerve sheath tumors (PNSTs). In human MPNSTs, PTEN expression is often reduced, while EGFR expression is often induced. We tested if these two genes cooperate in the evolution of PNSTs, because genetically modified mouse models for each gene alone resulted in the formation of low-grade PNSTs. Transgenic mice were generated carrying conditional floxed alleles of Pten, EGFR was expressed under the control of the 2′,3′-cyclic nucleotide 3’ phosphodiesterase (Cnp) promoter and a desert hedgehog (Dhh) regulatory element driving Cre recombinase transgenic mice (Dhh-Cre). Transgenic mice with EGFR overexpression and Pten inactivated have an early postnatal lethality (median survival age of 26-days) and displayed various peripheral nervous system phenotypes. These mice had multiple enlarged dorsal root ganglia, with high incidence of enlarged brachial plexus and trigeminal nerves at various stages of PNST tumorigenesis. In vitro experiments using immortalized human Schwann cells demonstrated that loss of PTEN and overexpression of EGFR cooperate to increase cellular proliferation and anchorage-independent colony formation. Taken together, our data suggests that reduced PTEN expression, together with EGFR overexpression, can drive malignant progression of low-grade to high-grade PNSTs. Importantly, our novel mouse model recapitulates sporadic human MPNST and will be useful for testing therapies to prevent or reverse tumor progression. Citation Format: Vincent W. Keng, Adrienne L. Watson, Eric P. Rahrmann, Hua Li, Barbara R. Tschida, Branden S. Moriarity, Kwangmin Choi, Tilat A. Rizvi, Margaret H. Collins, Margaret R. Wallace, Nancy Ratner, David A. Largaespada. Conditional inactivation of Pten and overexpression of EGFR in Schwann cells results in early high-grade peripheral nerve sheath tumor development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 354. doi:10.1158/1538-7445.AM2013-354