H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells.

Diffuse intrinsic pontine gliomas (DIPGs) are deadly pediatric brain tumors, non-resectable due to brainstem localization and diffusive growth. Over 80% of DIPGs harbor a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine-to-methionine substitution (H3K27M). Patients with DIPG have a dismal prognosis with no effective therapy. We show that histone deacetylase (HDAC) inhibitors lead to a significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines. We discover that the SB939-mediated H3.3K27M loss is partially blocked by a lysosomal inhibitor, chloroquine. The H3.3K27M loss is facilitated by co-occurrence of H2A.Z, as evidenced by the knockdown of H2A.Z isoforms. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. We discover a mechanism showing that HDAC inhibition in DIPG leads to pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings show the possibility of directly targeting the H3.3K27M oncohistone.

Middle temporal gyrus approach to mesial temporal lobe tumours in children.

AIM OF THE STUDY: To assess whether the middle temporal gyrus (MTG) approach to mesial temporal lobe (MTL) tumours is an effective procedure for the treatment of epilepsy in children. CLINICAL RATIONALE FOR THE STUDY: MTL tumours are a common cause of drug-resistant epilepsy in children. There is as yet no consensus regarding their treatment. One possibility is resection via a MTG approach. MATERIAL AND METHODS: We assessed the medical records of patients treated at the Department of Neurosurgery, Children's Memorial Health Institute,Warsaw, Poland between 2002 and 2020. A prospectively maintained database including clinical, laboratory, and radiographic presentation, as well as pre- and post-operative course, was analysed. Patients with at least a one- -year follow-up were included. RESULTS: There were 14 patients aged 4-18 years who underwent a MTG approach for a MTL tumour. All presented with epileptic seizure, and none had neurological deficit on admission to hospital. Median follow-up was 2.5 years. Neuronavigation was used to adjust the approach, localise the temporal horn, and achieve radical resection of the tumour and the hippocampus. Gross total resection was performed in all cases. In most patients, histopathological examination revealed ganglioglioma. One patient had transient aphasia. Two patients developed hemiparesis after surgery, which later improved. One of them also experienced visual disturbances. Acute complications were more frequent in younger patients (p = 0.024). In all cases, MRI confirmed complete resection and there was no tumour recurrence during the follow-up period. 13/14 patients remained seizure-free (Engel class I). CONCLUSIONS AND CLINICAL IMPLICATIONS: The MTG approach to MTL tumours is an effective procedure for the treatment of epilepsy in children. It avoids removal of the lateral temporal lobe and poses only a minor risk of permanent neurological complications.