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

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

doi:10.1172/jci44656

Cited by 70 publications

(68 citation statements)

References 16 publications

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“…Several studies have shown that ectopic expression of either RAF or BRAF alone is not sufficient to induce gliomas in mice (Lyustikman et al 2008;Robinson et al 2010;Gronych et al 2011), suggesting that BRAF may not be a driver mutation. However, BRAF expression was targeted to progenitor cells in the cerebral hemispheres rather than the more typical locations (cerebellum, optic pathway, and brainstem) where f-BRAF-containing PAs arise in children.…”

Section: Resultsmentioning

confidence: 99%

Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner

Kaul¹,

Chen²,

Emnett³

et al. 2012

Genes Dev.

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Tandem duplications involving the BRAF kinase gene have recently been identified as the most frequent genetic alteration in sporadic pediatric glioma, creating a novel fusion protein (f-BRAF) with increased BRAF activity. To define the role of f-BRAF in gliomagenesis, we demonstrate that f-BRAF regulates neural stem cell (NSC), but not astrocyte, proliferation and is sufficient to induce glioma-like lesions in mice. Moreover, f-BRAF-driven NSC proliferation results from tuberin/Rheb-mediated mammalian target of rapamycin (mTOR) hyperactivation, leading to S6-kinase-dependent degradation of p27. Collectively, these results establish mTOR pathway activation as a key growth regulatory mechanism common to both sporadic and familial low-grade gliomas in children.

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Section: Resultsmentioning

confidence: 99%

Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner

Kaul¹,

Chen²,

Emnett³

et al. 2012

Genes Dev.

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“…Indeed, overexpression of BRAF V600E using retrovirus, which might drive higher levels of BRAF activity or target higher numbers of suitable progenitors, is sufficient to produce pilocytic astrocytomas in mice (31).…”

Section: Cdkn2amentioning

confidence: 99%

Cooperative interactions of BRAF ^V600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy

Huillard

Hashizume

Phillips

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Although malignant astrocytomas are a leading cause of cancer-related death in children, rational therapeutic strategies are lacking. We previously identified activating mutations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) (BRAF T1799A encoding BRAF V600E ) in association with homozygous cyclin-dependent kinase inhibitor 2A (CDKN2A, encoding p14ARF and p16Ink4a) deletions in pediatric infiltrative astrocytomas. Here we report that BRAF V600E expression in neural progenitors (NPs) is insufficient for tumorigenesis and increases NP cellular differentiation as well as apoptosis. In contrast, astrocytomas are readily generated from NPs with additional Ink4a-Arf deletion. The BRAF V600E inhibitor PLX4720 significantly increased survival of mice after intracranial transplant of genetically relevant murine or human astrocytoma cells. Moreover, combination therapy using PLX4720 plus the Cyclin-dependent kinase (CDK) 4/6-specific inhibitor PD0332991 further extended survival relative to either monotherapy. Our findings indicate a rational therapeutic strategy for treating a subset of pediatric astrocytomas with BRAF V600E mutation and CDKN2A deficiency.glioma | protein kinase | tumor suppressor

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“…TaqMan MicroRNA Assay (Applied Biosystems) was used to verify the expression levels of candidate miRNAs (hsamiR-182, ABI assay ID 00597; hsa-miR-183, ABI assay ID 000484) as previously reported [7]. Expression levels of individual miRNAs were calculated using the 2[-delta delta C(T)] method [12] relative to the average expression level of two housekeeping small RNAs, RNU6B (ABI assay ID 001093) and RNU66 (ABI assay ID 001002), and a pooled normal cerebellum total RNA (24 male/female Caucasian, ages 16-70; Clontech).…”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

MicroRNA-182 promotes leptomeningeal spread of non-sonic hedgehog-medulloblastoma

et al. 2011

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The contribution of microRNAs to the initiation, progression, and metastasis of medulloblastoma (MB) remains poorly understood. Metastatic dissemination at diagnosis is present in about 30% of MB patients, and is associated with a dismal prognosis. Using microRNA expression profiling, we demonstrate that the retinal miR-183-96-182 cluster on chromosome 7q32 is highly overexpressed in non-sonic hedgehog MBs (non-SHH-MBs). Expression of miR-182 and miR-183 is associated with cerebellar midline localization, and miR-182 is significantly overexpressed in metastatic MB as compared to non-metastatic tumors. Overexpression of miR-182 in non-SHH-MB increases and knockdown of miR-182 decreases cell migration in vitro. Xenografts overexpressing miR-182 invaded adjacent normal tissue and spread to the leptomeninges, phenotypically reminiscent of clinically highly aggressive large cell anaplastic MB. Hence, our study provides strong in vitro and in vivo evidence that miR-182 contributes to leptomeningeal metastatic dissemination in non-SHH-MB. We therefore reason that targeted inhibition of miR-182 may prevent leptomeningeal spread in patients with non-SHH-MB.

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

Cited by 70 publications

References 16 publications

Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner

Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner

Cooperative interactions of BRAF ^V600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy

MicroRNA-182 promotes leptomeningeal spread of non-sonic hedgehog-medulloblastoma

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

Cited by 70 publications

References 16 publications

Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner

Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner

Cooperative interactions of BRAF V600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy

MicroRNA-182 promotes leptomeningeal spread of non-sonic hedgehog-medulloblastoma

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Cooperative interactions of BRAF ^V600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy