AI Article Synopsis
- DIPG is a deadly pediatric brain tumor, with about 25% of cases having ACVR1 mutations alongside H3.1K27M mutations, which influence tumor behavior.
- Experiments show that these mutations enhance certain markers and activate Stat3 signaling, but alone they don’t lead to full tumor development.
- Combining these mutations with PDGFA signaling worsens tumor outcomes, while treatment with Noggin or the ACVR1 inhibitor LDN212854 improves survival rates in DIPG models, highlighting LDN212854 as a potential treatment option.
Article Abstract
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.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399349 | PMC |
| http://dx.doi.org/10.1038/s41467-019-08823-9 | DOI Listing |
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