Fig. 2: Mechanisms of action of molecular and epigenetic alterations in malignant glioma.

Normally, IDH1 cooperates with NADP+ to convert isocitrate into α-ketoglutarate in the Krebs cycle. However, in IDH-mutant glioma, mutant-IDH cooperates with NADPH to convert α-KG into oncometabolite 2HG. Loss of function mutations in ATRX disrupt the function of the ATRX/DAXX complex to recruit and deposit histone variant H3.3 at sites of replication stress and DNA damage, ultimately leading to genomic instability in ATRX-deficient glioma. K27M mutations bind to and restrict the enzymatic activity of a core subunit of the PRC2, EZH2, sequestering PRC2, inhibiting the deposition of the repressive H3K27me3 mark, and ultimately causing transcriptional dysregulation in diffuse midline glioma. Lastly, G34R/V mutations inhibit the enzymatic activity of SETD2, a critical histone methylase, resulting in differential binding of K36 and disruption of H3K36me3 deposition, ultimately altering epigenetic and transcriptional regulation.