Abstract 2322: The KIAA1549:BRAF fusion gene regulates mTOR signaling and gliomagenesis in a cell type- and brain region-specific manner.

Abstract

Abstract The two most common genetic alterations in low-grade pediatric brain tumors (glioma) are NF1 gene inactivation and tandem duplications involving the BRAF kinase gene. In this study, we sought to define the role of KIAA1549:BRAF fusion (fusion BRAF; f-BRAF) gene in glioma development. We demonstrate that f-BRAF regulates cerebellar NSC proliferation by activating the mTOR pathway downstream of MAPK. Also, f-BRAF expression in cerebellar neuroglial progenitors is sufficient to induce glioma-like lesions in mice. Interestingly, f-BRAF expression does not increase the proliferation of NSCs derived from other brain regions, nor does it increase primary astrocyte proliferation. These brain region- and cell type-specific growth promoting effects of f-BRAF are mediated by tuberin/Rheb-dependent modulation of mTOR, leading to S6-kinase activation and p27 degradation. Finally, we demonstrate that mTOR activation is also observed in fusion BRAF-associated human sporadic pilocytic astrocytomas. Our findings highlight the importance of spatial, cellular and molecular heterogeneity in brain tumor development, and provide compelling preclinical evidence for the use of mTOR pathway inhibitors for both sporadic and familial low-grade gliomas. Citation Format: Aparna Kaul, Yi-Hsien Chen, Ryan J. Emnett, Sonika Dahiya, David Gutmann. The KIAA1549:BRAF fusion gene regulates mTOR signaling and gliomagenesis in a cell type- and brain region-specific manner. [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 2322. doi:10.1158/1538-7445.AM2013-2322