Mutations in chromatin machinery and pediatric high-grade glioma

Abstract

Pediatric central nervous system tumors are the most common solid tumor of childhood. Of these, approximately one-third are gliomas that exhibit diverse biological behaviors in the unique context of the developing nervous system. Although low-grade gliomas predominate and have favorable outcomes, up to 20% of pediatric gliomas are high-grade. These tumors are a major contributor to cancer-related morbidity and mortality in infants, children, and adolescents, with long-term survival rates of only 10 to 15%. The recent discovery of somatic oncogenic mutations affecting chromatin regulation in pediatric high-grade glioma has markedly improved our understanding of disease pathogenesis, and these findings have stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment. We review the current perspective on pediatric high-grade glioma genetics and epigenetics, and discuss the emerging and experimental therapeutics targeting the unique molecular abnormalities present in these deadly childhood brain tumors.

Keywords: DIPG; G34V/R; GSKJ4; Histone mutation; JMJD3; K27M; PRC2; demethylase; methyltransferase; pediatric high-grade glioma.

Fig. 1. Histone modifications by PRC2 methyltransferase and KDM demethylase activities, and associations with transcriptionally active versus inactive states.

Histone proteins are modified by the PRC2 methyltransferase and by KDM demethylase. PRC2 increases methylation of Lys²⁷, which promotes a more compact and transcriptionally repressed chromatin state. In contrast, KDM demethylase complex removes methyl groups from Lys²⁷ and increases methylation of Lys⁴ that, in combination, promote an open and transcriptionally active chromatin state.

Fig. 2. Neuroanatomic and gene associations with histone mutations.

K27M mutations are predominantly found in the tumors occurring in midline locations (thalamus, pons, and medulla oblongata). G34V or G34R (G34V/R) mutations are found in cerebral cortical tumors. Other gene alterations associated with histone gene mutations also occur in location-specific patterns. For example, TP53 mutations overlap with H3F3A mutations in cortical and thalamic tumors. ATRX and DAXX mutations are strongly associated with cortical G34V/R tumors and K27M mutant thalamic tumors, respectively. ACVR1 mutations are frequently present in histone H3.1 K27M mutant DIPG. OLIG1 and OLIG2 are highly expressed in K27M mutant tumors, whereas FOXG1 expression is predominantly found in G34V/R mutant tumors.

Fig. 3. Model for global reduction of H3K27 methylation in K27M DIPG, and effect of GSKJ4 on K27 methylation status.

Histone H3K27M mutant protein sequesters PRC2 histone methyltransferase and functionally inactivates it, leading to a global reduction of K27 methylation, thereby promoting an open chromatin structure that favors increased gene transcription. Pharmacological inhibition of JMJD3 H3K27 demethylase by GSKJ4 increases K27 methylation. In so doing, GSKJ4 suppresses gene expression and reduces tumor growth.