Chromatin mutations in pediatric high grade gliomas

Abstract

Pediatric high grade gliomas (HGG) are lethal tumors which are currently untreatable. A number of recent studies have provided much needed insights into the mutations and mechanisms which drive oncogenesis in pediatric HGGs. It is now clear that mutations in chromatin proteins, particularly H3.3 and its associated chaperone complex (ATRX), are a hallmark feature of pediatric HGGs. We review the current literature on the normal roles of the ATRX/H3.3 complex and how these functions are disrupted by oncogenic mutations. We discuss the current clinical trials and pre-clinical models that target chromatin and DNA, and how these agents fit into the ATRX/H3.3 mutation model. As chromatin mutations are a relatively new discovery in pediatric HGGs, developing clear mechanistic insights are a key step to improving therapies for these tumors.

Keywords: ATRX; DMG = diffuse midline glioma; H3.3 G34R/V; H3.3 K27M; KDM4; alternative lengthening of telomeres (ALT); histone H3.3; pediatric gliomas.

Figure 1

Key structural and functional features of histone H3.3. (A) DNA wrapped around nucleosome comprised of histones arranged into an octamer configuration with protruding tails. (B) Key features which distinguish histone variant H3.3 from canonical H3.1/2. (C) Selected amino acid residues on the H3.3 tail which are regulated by post-translational modifications. Red boxes show the position of frequently mutated residues. Grey ovals represent examples of epigenetic readers, writers, and erasers known to interact with mutated and surrounding residues.