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This document, published in Acta Neuropathologica Communications, discusses the identification of a subtype of diffuse midline glioma (DMG) called H3K27/MAPKinase co-altered. The study analyzes a cohort of 182 pediatric and adult cases of DMG, H3K27-altered and identifies 30 tumors with a loss of ATRX expression. The authors provide clinical, histopathological, and molecular data on these tumors and suggest that the loss of ATRX expression may be a potential diagnostic tool for identifying DMG, H3K27/MAPK co-altered. The study highlights the distinct features of this subtype and emphasizes the importance of integrating clinical, radiological, histopathological, and molecular results for an accurate diagnosis. [Extracted from the article]

We previously identified VRK3 as a specific vulnerability in DMG-H3K27M cells in a synthetic lethality screen targeting the whole kinome. The aim of the present study was to elucidate the mechanisms by which VRK3 depletion impact DMGH3K27M cell fitness. Gene expression studies after VRK3 knockdown emphasized the inhibition of genes involved in G1/S transition of the cell cycle resulting in growth arrest in G1. Additionally, a massive modulation of genes involved in chromosome segregation was observed, concomitantly with a reduction in the level of phosphorylation of serine 10 and serine 28 of histone H3 supporting the regulation of chromatin condensation during cell division. This last effect could be partly due to a concomitant decrease of the chromatin kinase VRK1 in DMG following VRK3 knockdown. Furthermore, a metabolic switch specific to VRK3 function was observed towards increased oxidative phosphorylation without change in mitochondria content, that we hypothesized would represent a cell rescue mechanism. This study further explored the vulnerability of DMG-H3K27M cells to VRK3 depletion suggesting potential therapeutic combinations, e.g. with the mitochondrial ClpP protease activator ONC201. [ABSTRACT FROM AUTHOR]