A pontine-specific axonal niche supports de novo gliomagenesis

Abstract

AbstractDiffuse intrinsic pontine gliomas (DIPGs), a major type of pediatric high-grade gliomas located in the pons, are the leading cause of death in children with brain cancer. A subset (20-25%) of DIPGs harbor a lysine 27-to-methionine (K27M) mutation inHIST1H3B, which encodes histone H3.1, and an activatingACVR1mutation. The occurrence of this pair of mutations in DIPGs, but not in pediatric gliomas in other anatomical locations, suggests the existence of a pontine-specific niche that favors DIPG gliomagenesis. Unfortunately, the identity of the underlying pontine niche remains elusive as available mouse models fail to recapitulate the anatomic specificity that characterizes DIPGs. Herein we show that the trigeminal root entry zone (TREZ), a pontine structure where several major axon tracts intersect, is enriched with proliferating oligodendrocyte-lineage cells during brainstem development. Introducing bothH3.1K27Mand activatingAcvr1andPik3camutations (which co-occur frequently withH3.1K27Min human DIPGs) into the mouse brain leads to rapid gliomagenesis. This pathology recapitulates the pons specificity of DIPGs as glioma cells proliferate on axon tracts at the TREZ. We further show that a hyaluronan receptor important for cell stemness (HMMR) plays a key role in glioma cell proliferation at the TREZ. We propose thatH3.1K27Mand its co-occurring mutations drive pontine specific gliomagenesis by inducing a proliferative response of oligodendrocyte-lineage cells with enhanced stemness on large TREZ axon tracts.One-Sentence SummaryThe trigeminal root entry zone underlies pontine-specific gliomagenesis driven byH3.1K27Mand its co-occurring mutations.