Abstract
The f-BRAF fusion protein enhances NSC growth and gliomagenesis in a cell-type–specific manner.
Major finding: The f-BRAF fusion protein enhances NSC growth and gliomagenesis in a cell-type–specific manner.
Mechanism: f-BRAF induces RHEB-mediated activation of mTORC1 and S6K, which triggers p27 degradation.
Impact: mTOR inhibition may improve the treatment of both sporadic and familial pediatric gliomas.
Sporadic low-grade pilocytic astrocytoma (PA) is a common subtype of childhood glioma frequently associated with expression of the KIAA1549:BRAF fusion gene. However, although the resulting BRAF fusion protein (f-BRAF) exhibits increased kinase activity, its contribution to gliomagenesis remains unclear. To address this question, Kaul and colleagues expressed f-BRAF specifically in murine neural stem cells (NSC) derived from the cerebellum, a major site of sporadic PA tumors. Expression of this fusion protein resulted in increased MAPK activation and NSC proliferation. In contrast, f-BRAF did not increase the proliferation of astrocytes or cortical NSCs, highlighting the cell-type and brain-region specificity of this genetic change. Consistent with this idea, engraftment of f-BRAF–expressing NSCs generated proliferative glioma-like lesions in mouse cerebella, and MAPK and mTOR activation was correlated with f-BRAF expression in human sporadic PA samples. Mechanistically, f-BRAF stimulated phosphorylation of S6 kinase (S6K) and ribosomal protein S6 in NSCs but not astrocytes, indicative of mTOR activation. Induction of mTOR signaling was mediated by MEK-dependent inactivation of tuberin, a component of the tuberous sclerosis complex (TSC) that negatively regulates mTOR, and subsequent activation of the RAS homolog enriched in brain (RHEB) GTPase. In addition, f-BRAF expression in cerebellar NSCs led to increased S6K- and cyclin-dependent kinase 2 (CDK2)–driven phosphorylation and degradation of the CDK inhibitor p27Kip1, suggesting that f-BRAF promotes NSC proliferation via this mTORC1 signaling cascade. These results define an oncogenic function for the f-BRAF fusion in specific cell types from particular brain regions relevant to the patterning of gliomagenesis in children and identify inhibition of the mTOR pathway, which is also induced in familial PA tumors characterized by loss of the NF1 tumor suppressor, as a potential therapeutic strategy for the treatment of both sporadic and familial PA.
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