Shared ACVR1 mutations in FOP and DIPG: Opportunities and challenges in extending biological and clinical implications across rare diseases

Abstract

Gain-of-function mutations in the Type I Bone Morphogenic Protein (BMP) receptor ACVR1 have been identified in two diseases: Fibrodysplasia Ossificans Progressiva (FOP), a rare autosomal dominant disorder characterized by genetically driven heterotopic ossification, and in 20-25% of Diffuse Intrinsic Pontine Gliomas (DIPGs), a pediatric brain tumor with no effective therapies and dismal median survival. While the ACVR1 mutation is causal for FOP, its role in DIPG tumor biology remains under active investigation. Here, we discuss cross-fertilization between the FOP and DIPG fields, focusing on the biological mechanisms and principles gleaned from FOP that can be applied to DIPG biology. We highlight our current knowledge of ACVR1 in both diseases, and then describe the growing opportunities and barriers to effectively investigate ACVR1 in DIPG. Importantly, learning from other seemingly unrelated diseases harboring similar mutations may uncover novel mechanisms or processes for future investigation.

Keywords: ACVR1; BMP; Childhood cancers; Diffuse Intrinsic Pontine Glioma; Fibrodysplasia Ossificans Progressiva; Mendelian disorders.

Figure 1. Differences in ACVR1 mutations identified in Fibrodysplasia Ossificans Progressiva (FOP) and Diffuse Intrinsic Pontine Gliomas (DIPG)

(A) ACVR1 mutations found in FOP (black), DIPG (green), or both diseases (red). All are located in the intracellular receptor domains, either the glycine-serine rich (GS, purple) or protein kinase (blue) domain. Of the seven DIPG-associated ACVR1 mutations, six have been identified in FOP. (B) Prevalence of ACVR1 mutations in FOP and DIPG taken from the four initial studies identifying ACVR1 in DIPG. While the R206H mutation occurs in 95–97% of FOP patients, the spectrum of ACVR1 mutations in DIPG is more varied.

Figure 2. Model systems for Fibrodysplasia Ossificans Progressiva (FOP) and Diffuse Intrinsic Pontine Gliomas (DIPGs) to study ACVR1

(A) In FOP, lesions initially undergo muscle breakdown and infiltration of immune cells prior to the formation of a chondrogenic scaffold and subsequent bone formation. Genetically engineered mouse models expressing the R206H mutation recapitulate this full lesion progression. Furthermore, in vitro R206H cell-based models faithfully recapitulate the chondrogenic and osteogenic phases of heterotopic ossification when placed in permissive differentiation media. Thus, the full spectrum of lesion progression is recapitulated in laboratory model systems. (B) In contrast, current DIPG models that harbor ACVR1 mutations consist mainly of patient-derived DIPG tumor cell lines, many of which are derived from patients whom already received chemoradiation. There are few reported cell-based and transgenic animal models for DIPG, though generation of brainstem tumors after expression of ACVR1 and co-mutations has yet to be reported. Given these limitations, our ability to effectively study ACVR1 is hampered by our inability to fully model the oncogenic process. FOP skeleton image courtesy of Dr. Frederick Kaplan, University of Pennsylvania; T2 FLAIR MRI image courtesy of Dr. Angela Waanders, Children’s Hospital of Philadelphia.

Figure 3. Multiple phenotypes for analysis in Diffuse intrinsic pontine gliomas (DIPGs)

(Left) In FOP, ACVR1 and elevated BMP signaling is both necessary and sufficient for heterotopic ossification (HO). This has led to the development of multiple model systems with a consistent, reproducible phenotype. Although the cell type origin of HO remains unclear, recent studies identified Scleraxis+ and Msx1+ cells as sufficient to form heterotopic bone in the presence of ACVR1 mutations. (Right) In contrast, the role of ACVR1 mutations in DIPG remains unclear. In particular, we have yet to identify a tumor-associated phenotype(s) impacted by ACVR1 mutations. While tumor growth and tumor proliferation remains a key phenotype for cancers, there are other important oncogenic features that should be examined. Importantly, understanding the role of ACVR1 in DIPG is complicated by co-mutations present in ACVR1 mutant DIPGs, such as K27M substitution in Histone 3 variants. In addition, the cell of origin of DIPG remains unclear and each potential cell type origin has pleotropic responses to BMP signaling.