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Series GSE125627 Query DataSets for GSE125627
Status Public on Jan 25, 2019
Title RNAseq of nestin-expressing murine brainstem progenitors infected with ACVR1 WT or R206H ACVR1 with and without H3.1K27M
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, resulting in the death of 200-300 children each year in the United States. Recently it was discovered that approximately 25% of all DIPG cases harbor activating mutations in ACVR1, a gene that encodes Activin A receptor (ALK2), a receptor in the bone morphogenetic protein (BMP) pathway, and that DIPGs with ALK2 mutations commonly harbor an H3.1K27M mutation. Herein, we used the RCAS/TVA retroviral system to study the effects of ACVR1 mutations and H3.1K27M on DIPG pathogenesis. In vitro expression of R206H ACVR1 with and without H3.1K27M in nestin-expressing brainstem progenitors resulted in upregulation of mesenchymal markers and gene set enrichment analysis (GSEA) revealed Stat3 pathway activation. Neonatal expression of ACVR1 R206H or G328V in combination with H3.1K27M and p53 deletion in nestin-expressing brainstem progenitors induced glioma-like lesions expressing mesenchymal markers with Stat3 activation but was not sufficient for full gliomagenesis. In combination with platelet-derived growth factor A (PDGFA) signaling, ACVR1 R206H and H3.1K27M significantly decreased survival and increased tumor incidence. We demonstrate that targeting the BMP signaling pathway may be an effective therapeutic strategy to treat ACVR1 R206H mutant DIPGs. Exogenous Noggin expression at tumor initiation significantly increased tumor latency and treatment of ACVR1 R206H mutant murine DIPGs with LDN212854, an ACVR1 inhibitor, significantly prolonged their survival. We confirm relevance of our model to the human disease as human DIPG models with ACVR1 mutations were also sensitive to treatment with LDN212854 in vitro. Altogether, our studies demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile in part due to Stat3 activation, and identify LDN212854 as a promising compound to treat children with DIPG.
Overall design We use RNAseq to study the transcriptomal effects of ACVR1 WT or R206H ACVR1 mutation alone and in combination with H3.1K27M mutation on murine nestin-expressing brainstem progenitors at P3-5 (using RCAS/TVA). Key findings were validated by Real-Time PCR.
Contributor(s) Becher O, Hoeman C, Gadd S
Citation(s) 30833574
Submission date Jan 24, 2019
Last update date Apr 20, 2022
Contact name Oren Josh Becher
Phone 212-241-7605
Organization name Mount Sinai
Department Pediatrics
Lab Becher Lab
Street address 1468 Madison Avenue, A21-02
City New York
State/province NY
ZIP/Postal code 10029
Country USA
Platforms (1)
GPL9185 Illumina Genome Analyzer (Mus musculus)
Samples (12)
GSM3579107 human ACVR1 1
GSM3579108 human ACVR1 2
GSM3579109 human ACVR1 3
BioProject PRJNA516939
SRA SRP181955

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Supplementary file Size Download File type/resource
GSE125627_RAW.tar 2.3 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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