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An activated mutant BRAF kinase domain is sufficient to induce pilocytic astrocytoma in mice
Jan Gronych, … , Stefan Pfister, Peter Lichter
Jan Gronych, … , Stefan Pfister, Peter Lichter
Published March 14, 2011
Citation Information: J Clin Invest. 2011;121(4):1344-1348. https://doi.org/10.1172/JCI44656.
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Brief Report Oncology

An activated mutant BRAF kinase domain is sufficient to induce pilocytic astrocytoma in mice

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Abstract

Pilocytic astrocytoma (PA) is the most common type of primary brain tumor in children and the second most frequent cancer in childhood. Children with incompletely resected PA represent a clinically challenging patient cohort for whom conventional adjuvant therapies are only moderately effective. This has produced high clinical demand for testing of new molecularly targeted treatments. However, the development of new therapeutics for PA has been hampered by the lack of an adequate in vivo tumor model. Recent studies have identified activation of MAPK signaling, mainly by oncogenic BRAF activation, as a hallmark genetic event in the pathogenesis of human PA. Using in vivo retroviral somatic gene transfer into mouse neural progenitor cells, we have shown here that ectopic expression of the activated BRAF kinase domain is sufficient to induce PA in mice. Further in vitro analyses demonstrated that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with the kinase inhibitor sorafenib. Our in vivo model for PA shows that the activated BRAF kinase domain is sufficient to induce PA and highlights its role as a potential therapeutic target.

Authors

Jan Gronych, Andrey Korshunov, Josephine Bageritz, Till Milde, Manfred Jugold, Dolores Hambardzumyan, Marc Remke, Christian Hartmann, Hendrik Witt, David T.W. Jones, Olaf Witt, Sabine Heiland, Martin Bendszus, Eric C. Holland, Stefan Pfister, Peter Lichter

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Figure 1

BRAF variants induce MAPK activation.

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BRAF variants induce MAPK activation.
(A) Different BRAF constructs used...
(A) Different BRAF constructs used for RCAS-mediated gene delivery. Truncated variants containing the kinase domain corresponded to exons 9–18 of the human BRAF gene. The V600E mutation is indicated. (B) Phase-contrast microscopy demonstrated altered cell morphology and focal growth of cells transduced with BRAF VE kin compared with control and other BRAF constructs. Scale bars: 100 μm.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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