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

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.

Differential kinase activity of ACVR1 G328V and R206H mutations with implications to possible TβRI cross-talk in diffuse intrinsic pontine glioma

“…1b, 3c, Supplementary Fig. 3b), agrees with previous phenotypic studies using ACVR1 transfected DIPG and FOP mouse cell models to compare signaling activities of different ACVR1 mutants and wild-type 12,25 . These studies showed that G328V expression caused higher Smad/1/5/8 phosphorylation and downstream target gene ID1 expression levels in the DIPG cell model or downstream luciferase reporter gene expression levels in the FOP cell model than R206H and wild-type, either constitutively or upon specific extracellular stimulations such as Activin A 12,25 .…”

“…Although there clearly exists a high frequency of ACVR1 somatic mutations in DIPG patients 5,14,15 and the demonstrated preclinical potency of ACVR1 inhibitors at a µM level to inhibit DIPG cells with different biological backgounds 2,12 , we suggest that additional target validation and mechanistic studies of ACVR1 and associated pathways for DIPG therapeutics are required for the following reasons: First, the G328E/V/W mutations correlate with longer patient survival 2,15 . At least for the G328V mutation, its better prognosis might be due to increased kinase activity ( Fig.…”

“…The understanding of the genetic and epigenetics context of DIPG led to therapeutic efforts that targeted chromatin modifiers such as histone deacetylase (HDAC), demethylase or methyltransferase complexes 6,[8][9][10][11] as well as kinases such as ACVR1 (also called ALK2) 2,12 . These studies yielded promising preclinical efficacy of single agent or combinations in different DIPG cell and mice xenograft models.…”

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

“…Moreover, a recent study shows that in particular ACVR1 R206H mutants induce a mesenchymal phenotype by STAT3 signaling activation and associate with shorter survival (49). This seems to indicate that distinct ACVR1 mutations have differential effects on DIPG tumor progression as other non-R206H mutants have been associated with longer survival rate (23).…”

“…In addition, BMP induced RAS/MAPK signaling increases transcription of SNAI1/2 and phosphorylates TWIST1 (52,53) and JAK/STAT activation up-regulates all three EMT related transcription factors (54)(55)(56). Indeed, when brainstem progenitor cells were transduced with DIPG associated mutations in ACVR1, SMAD phosphorylation, STAT3 signaling, and mesenchymal marker expression were induced (49). In addition, a meeting abstract reports that inhibition of the JAK/STAT component STAT3 in human DIPG cell lines results in a reduced migratory phenotype (57).…”