Abstract Introduction: Survivin expression correlates with poor prognosis in high-grade glioma. The influence of Survivin isoforms on outcome is poorly understood. We analyzed the dominant anti-apoptotic transcript variants of Survivin using expression data and modeled them in vivo. Methods: TCGA mRNA expression data was used to study Survivin in low- and high-grade gliomas including proneural(PN) and mesenchymal(Mes) subtypes. We expressed the anti-apoptotic isoforms of Survivin (transcript variants 1 and 2) in vivo using the RCAS/Ntv-a system. Results: In low-grade glioma, increased expression of Survivin occurred in 22/167(13.2%) cases, and was associated with shortened survival (log rank test, p=0.005). In high-grade gliomas, increased expression occurred in 258/547(47%) cases. Variant 1 was expressed in 215/258(83%) cases, and variant 2 was expressed in 26/258(10%) cases. Median survival was 451 days and 382 days for variant 1 and 2 expressors respectively. Survivin was preferentially expressed in PN relative to Mes gliomas(chi squared, p<0.0001). In PN gliomas, Survivin was expressed in 94/141(67%) cases which had shorter progression free survival(log rank test, p=0.04). Median survival in PN gliomas was 447 days for Variant 1 expressors and 394 days for Variant 2 expressors. In mice, ectopic expression of variant 1 yielded tumors in 28/30(93%) of mice and only 7/28(25%) were high-grade. Ectopic expression of Variant 2 yielded tumors in 27/28(96%) of mice and the majority (22/27,(81%)) were high grade(chi squared, p<0.0001). CD31 expression (to quantify angiogenesis) was significantly higher in Variant 2-derived tumors than Variant 1(t test, p<0.0001). Tumor free survival was shorter in mice with variant-2 derived tumors(log rank test, p=0.01) Conclusions: Survivin expression in low-grade gliomas is associated with poor survival and is more common in PN gliomas. Poorer survival correlates with Survivin Variant 2, relative to the common isoform. In a PN murine glioma model, variant 2 promotes malignant progression, angiogenesis and shortens tumor-free survival. Note: This abstract was not presented at the conference. Citation Format: Ganesh Rao, Tiffany Doucette, Yuhui Yang, Greg Fuller, Arvind Rao. The Survivin-deltaEx3 isoform drives microvascular proliferation and malignant progression in proneural gliomas. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B32.