Abstract
High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in gliomagenesis such that BSG is considered a distinct disease from glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the brainstem gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in glioma. Ectopic expression of Pax3 in normal brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced brainstem gliomagenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0134-6) contains supplementary material, which is available to authorized users.
Highlights
Brainstem Glioma (BSG) is a brain tumor that arises anywhere in the brainstem, and is seen predominately in children
Mouse Brainstem Glioma and Cerebral Cortex Glioma have distinct gene expression signatures In order to identify regional differences in glioma, and in particular unique characteristics of those arising in the brainstem, we generated mouse Brainstem Glioma (BSG) and Cerebral Cortex Glioma (CG) by injecting RCASPDGF-B virus-producing cells into the brainstem or cerebral cortex, respectively, of postnatal day 2–4 (P2-4) Nestin-Tv-a(Ntv-a);Ink4aARF−/− mice (Figure 1a) [34,43]
Using an False Discovery Rate (FDR)-adjusted p-value
Summary
Brainstem Glioma (BSG) is a brain tumor that arises anywhere in the brainstem, and is seen predominately in children. The majority of BSG (80-85%) are high grade, diffuse, and are located in the pons—these are known as Diffuse Intrinsic Pontine Glioma (DIPG) and have an overall survival of less than one year [1]. Previous work on BSG has characterized distinct subsets of the disease, including mesenchymal and oligodendroglial [5], N-Myc and Hedgehog [17], MYCN, silent, and H3-K27M [10] or H3-K27M and wildtype [6]. Together, these classifications highlight the heterogeneity of this disease and the likelihood that effective treatment will require an understanding of the mechanisms driving the growth of each individual subtype
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