Abstract
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 ACVR1mutations, 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 ACVR1 R206H with and without H3.1K27M in nestin-expressing brainstem progenitors resulted in upregulation of mesenchymal markers and revealed Stat3 activation by gene set enrichment analysis (GSEA) analysis. 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 along with Stat3 activation but were not sufficient for full gliomagenesis in vivo. 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 may be an effective therapeutic strategy to treat ACVR1 R206H mutant DIPGs as 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.