ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis
| Autor: | Javad Nazarian, Guo Hu, Herminio J. Cardona, Daniele Procissi, Paul B. Yu, Rintaro Hashizume, Roger E. McLendon, Megan M. Romero, Samantha Gadd, Oren J. Becher, Katie Misuraca, Francisco Cordero, Christine M. Hoeman |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
General Physics and Astronomy 02 engineering and technology Tumor initiation medicine.disease_cause Histones Mice Medicine Brain Stem Neoplasms lcsh:Science Regulation of gene expression Platelet-Derived Growth Factor Mutation Multidisciplinary Glioma 021001 nanoscience & nanotechnology 3. Good health Gene Expression Regulation Neoplastic Quinolines Signal transduction 0210 nano-technology Signal Transduction STAT3 Transcription Factor Science Astrocytoma General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences In vivo Cell Line Tumor Animals Humans Noggin Cell Proliferation Cell growth business.industry Genome Human Gene Expression Profiling Mesenchymal stem cell General Chemistry Disease Models Animal 030104 developmental biology Pyrimidines Cancer research Pyrazoles lcsh:Q business Carrier Proteins Activin Receptors Type I |
| Zdroj: | Nature Communications Nature Communications, Vol 10, Iss 1, Pp 1-15 (2019) |
| ISSN: | 2041-1723 |
| Popis: | Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG. ACVR1 and H3.1K27M mutations co-occur in diffuse intrinsic pontine glioma. Here, the authors generate a mouse model that recapitulates these genetic lesions and show, using genetic and pharmacological approaches, that the bone morphogenetic protein pathway may be a therapeutic target in these tumours. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|