ACVR1-Mutant diffuse intrinsic pontine gliomas (DIPGS) acquire abeerant activin-mediated bmp pathway activation
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric high-grade gliomas with no effective therapies. In 20-25% of DIPGs, seven gain-of-function mutations were identified in the Type 1 Bone Morphogenic Protein (BMP) receptor ACVR1 (also known as ALK2). All mutations result in weak ligand-independent BMP pathway activation and enhanced responsiveness to exogenous BMPs. Intriguingly, germline ACVR1 mutations underlie Fibrodysplasia Ossificans Progressiva (FOP), a non-cancerous autosomal dominant disorder characterized by spontaneous or injury-induced extra-skeletal bone formation. Recent FOP studies demonstrated that the most common FOP mutation, the ACVR1-R206H substitution, imparts novel responsiveness and abnormal BMP pathway activation to the inhibitory ligand activin. In addition, these studies suggest that activin-mediated ACVR1 signaling is important in pathologic bone formation. In this ongoing study, we assessed whether abnormal activin responsiveness also occurs in DIPGs and if this aberrant BMP signaling impacts tumor-related phenotypes. We found that activin differentially increased BMP signaling in ACVR1-mutant DIPG patient-derived tumor lines. Furthermore, we assessed known DIPG-associated ACVR1 mutations and found that all mutations aberrantly activated BMP signaling after activin exposure, indicating that acquired ligand responsiveness is conserved across ACVR1 mutations. We are currently assessing the potential impact of abnormal signaling on oncogenic phenotypes. Overall, our data demonstrate that ACVR1-mutant DIPGs and DIPG-associated ACVR1 mutations acquire aberrant BMP pathway activation after activin exposure, raising the possibility that novel responsiveness to a non-canonical ligand may be an unexplored mechanism and potential therapeutic target for DIPGs. Additionally, our study highlights the value of cross-fertilization between seemingly unrelated rare pediatric diseases.