title: The BRAF kinase domain promotes the development of gliomas in vivo.
abstract: In-frame BRAF fusions have been observed in over 80% of sporadic pilocytic astrocytomas. In each fusion, the N-terminal autoinhibitory domain of BRAF is lost, which results in constitutive activation via the retained C-terminal kinase domain (BRAF-KD). We set out to determine if the BRAF-KD is sufficient to induce gliomas alone or in combination with Ink4a/Arf loss. Syngeneic cell lines demonstrated the transforming ability of the BRAF-KD following Ink4a/Arf loss. In vivo, somatic cell gene transfer of the BRAF-KD did not cause tumors to develop; however, gliomas were detected in 21% of the mice following Ink4a/Arf loss. Interestingly, these mice demonstrated no obvious symptoms. Histologically the tumors were highly cellular and atypical, similar to BRAF(V600E) tumors reported previously, but with less invasive borders. They also lacked the necrosis and vascular proliferation seen in BRAFV600E-driven tumors. The BRAF-KD-expressing astrocytes showed elevated MAPK signaling, albeit at reduced levels compared to the BRAF(V600E) mutant. Pharmacologic inhibition of MEK and PI3K inhibited cell growth and induced apoptosis in astrocytes expressing BRAF-KD. Our findings demonstrate that the BRAF-KD can cooperate with Ink4a/Arf loss to drive the development of gliomas and suggest that glioma development is determined by the level of MAPK signaling.
authors.affiliation: Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah, USA ; Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
authors.forename: Clifford H
authors.initials: CH
authors.lastname: Shin
authors.affiliation: Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA ; ARUP Laboratories, Salt Lake City, Utah, USA.
authors.forename: Allie H
authors.initials: AH
authors.lastname: Grossmann
authors.affiliation: Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah, USA ; Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah, USA ; Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Holmen
authors.affiliation: Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Robinson
keywords: BRAF; Ink4a/Arf; RCAS/TVA; glioma; mouse model
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