ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis

Christine M Hoeman,Francisco J Cordero,Katie Misuraca,Samantha Gadd,Paul Yu,Guo Hu,Javad Nazarian,Oren J Becher,Megan M Romero,Daniele Procissi,Roger Mclendon,Herminio J Cardona,Rintaro Hashizume

doi:10.1038/s41467-019-08823-9

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.

Highlights

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
We have examined ACVR1 mutations in vitro using the RCAS/tva system with brainstem progenitor cells cultured as adherent cell lines[6]
Previous studies support the idea of bone morphogenetic protein (BMP) signaling as a tumor suppressor pathway in gliomas as it has been shown to block the proliferation of neural stem cells and glioma-initiating cells[32]

Summary

Introduction

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. Our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat[3] activation, and identify LDN212854 as a promising compound to treat DIPG. While ACVR1 mutations can lead to the formation of glioma-like lesions, with H3.1K27M and p53 loss being required for this process, such genetic alterations are not sufficient to drive tumor development. We identify the BMP signaling pathway as a potential effective therapeutic strategy to treat ACVR1 R206H mutant DIPGs as exogenous Noggin expression at tumor initiation or treatment with LDN212854 significantly increases tumor latency and prolongs survival. We validate our observations in human models by demonstrating that human ACVR1 mutant DIPG cell-lines are sensitive to treatment with LDN212854 in vitro and that human tumors with ACVR1 mutations harbor increased Stat[3] signaling. This study highlights the role of mutant ACVR1 and H3.1K27M in tumor initiation and identifies the BMP pathway, LDN212854, as a promising therapeutic agent for further evaluation in ACVR1 mutant DIPG

Methods

Results

Conclusion