ACVR1 mutations in DIPG: lessons learned from FOP

Abstract

Whole-genome sequencing studies have recently identified a quarter of cases of the rare childhood brainstem tumor diffuse intrinsic pontine glioma to harbor somatic mutations in ACVR1. This gene encodes the type I bone morphogenic protein receptor ALK2, with the residues affected identical to those that, when mutated in the germline, give rise to the congenital malformation syndrome fibrodysplasia ossificans progressiva (FOP), resulting in the transformation of soft tissue into bone. This unexpected link points toward the importance of developmental biology processes in tumorigenesis and provides an extensive experience in mechanistic understanding and drug development hard-won by FOP researchers to pediatric neurooncology. Here, we review the literature in both fields and identify potential areas for collaboration and rapid advancement for patients of both diseases.

Figure 1. ACVR1 mutations link FOP and DIPG

(A) Left: Dorso-ventral computed tomography (CT) scan image showing extensive heterotopic bone formation in the skeletal muscles of an aged individual with FOP. (Courtesy of James T. Triffitt, Martyn Cooke and Margot Rintoul). Right: T2 weighted sagittal magnetic resonance imaging (MRI) scan of an individual with DIPG at time of diagnosis (Courtesy of Darren Hargrave) (B) Schematic representation of ACVR1 mutations in FOP and DIPG. Protein structure is given highlighting ligand binding (grey), GS (green) and kinase (purple) domains. Amino acid substitutions identified to date in FOP (blue), DIPG (red) or both diseases (purple) are labelled. (C) Cartoon representing a simplified BMP/ALK2 signalling pathway. ALK2 is a type I BMP receptor which dimerises, and upon ligand binding forms a heteromeric complex with two type II receptors (e.g. BMPRII), which themselves phosphorylate the ALK2 GS domain. Mutations (yellow stars) in either the GS or kinase domains inhibit interactions with the negative regulator FKBP12 and enhance recruitment and phosphorylation of SMAD1/5/8. Both types of mutation therefore confer constitutive pathway activation as evidenced by increased expression of transcriptional targets of the SMAD1/5/8 and SMAD4 complex in the nucleus. Small molecules such as dorsomorphin and LDN-193189 may be useful therapeutic strategies aimed at inhibiting the activation of this pathway. ACVR1 mutations co-segregate in DIPG with histone H3.1 K27M mutations, which enhance transcription via disruption of trimethylated lysine 27 interactions with the repressive PRC2 complex. This de-repression of gene expression may include common targets with SMAD signalling including ID1 and ID2.