Recent work has identified novel point mutations in isocitrate dehydrogenase 1 (IDH1) in the majority of the World Health Organization grades II and III infiltrative gliomas and secondary grade IV ...glioblastomas. Gangliogliomas consist of neoplastic ganglion and glial cells and, in contrast to infiltrative gliomas, are generally indolent. Yet distinguishing between a ganglioglioma and an infiltrative glioma with admixed gray matter can be difficult, perhaps accounting for some “gangliogliomas” that ultimately show aggressive behavior. In this multi‐institutional study, 98 cases originally diagnosed as ganglioglioma were analyzed for IDH1 mutations, 86 of which had follow‐up data available. Eight cases (8.2%) were positive for R132H IDH1 mutations; six had silent IDH2 mutations and two had nonsense IDH2 mutations. The presence of mutant IDH1 in gangliogliomas correlated with a greater risk of recurrence (P = 0.0007) and malignant transformation and/or death (P < 0.0001) compared with tumors that were IDH1 wild type. Furthermore, the age of patients with IDH1‐mutant gangliogliomas was higher than those without mutations (25.5 vs. 46.1 years, P = 0.0033). IDH1/2 testing of tumors suspected of being gangliogliomas may therefore be advisable, particularly in the adult population.
Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in ...any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Panwalkar P, Clark J, Ramaswamy V, Hawes D, Yang F, Dunham C, Yip S, Hukin J, Sun Y, Schipper MJ et al (2017) Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-a childhood posterior fossa ependymoma and is a powerful predictor of outcome. Piunti A, Smith ER, Morgan MAJ, Ugarenko M, Khaltyan N, Helmin KA, Ryan CA, Murray DC, Rickels RA, Yilmaz BD et al (2019) CATACOMB: an endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism.
Glioblastomas are lethal malignancies that possess a rapidly evolving microenvironment containing necrotic/hypoxic areas, aberrant microvasculature, and glioblastoma stem cells (GSCs) that promote ...tumor growth, recurrence, and treatment resistance. Chen et al. find that GSCs drive integrated epigenetic and metabolic control of angiogenesis via histamine and propose antihistamines as potential therapies.
Glioblastomas are lethal malignancies that possess a rapidly evolving microenvironment containing necrotic/hypoxic areas, aberrant microvasculature, and glioblastoma stem cells (GSCs) that promote tumor growth, recurrence, and treatment resistance. Chen et al. find that GSCs drive integrated epigenetic and metabolic control of angiogenesis via histamine and propose antihistamines as potential therapies.
Abstract HIV encephalitis (HIVE) is characterized by neurodegeneration mediated by toxins derived from infected and activated brain macrophages. Since the peripheral benzodiazepine receptor (PBR) is ...abundant on brain macrophages, we hypothesized that 3 HDAA1106, a new PBR ligand, can label infected and activated brain macrophages in HIVE. Using cell culture and postmortem brain tissues from HIVE and a macaque model of HIVE, we show that 3 HDAA1106 binds with high affinity to activated and infected macrophages in regions of synaptic damage. Further, binding affinity reflected by lower KD (dissociation constant) values and the Bmax (total number of binding sites) to KD ratios reflective of ligand-binding potential was significantly higher with 3 HDAA1106 compared to the extensively characterized PBR ligand 3 H(R)-PK11195. These data suggest that DAA1106 binds with high affinity to activated and infected brain macrophages and possesses binding characteristics beneficial for in vivo use in the detection and clinical monitoring of HIVE using positron emission tomography.
In the solid component within the pons, ependymal rosettes, perivascular pseudorosettes (Fig. 1d, e) and focal areas of astroblastic rosettes occasionally surrounding hyalinized blood vessels ...suggestive of ependymal differentiation were encountered. ...this tumor poses a challenge for neuropathologists as the diagnosis rendered may vary based both on where the tumor was biopsied (solid vs infiltrative nodules) and their interpretation of the current WHO classification and cIMPACT-NOW guidelines. In summary, this unusual brain tumor arising within the pons clinically met the criteria for a DIPG but upon biopsy examination demonstrated H3K27me3 global reduction, EZHIP overexpression and methylation profile that cluster with group ‘EPN, PFA’ despite a lack of apparent ependymal histologic features 5.
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to ...methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT) but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain.
We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and our models, quantified purine synthesis using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT.
DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novo synthesis and apparent lower activity of purine salvage demonstrated via stable isotope tracing of key metabolites in purine synthesis and by lower expression of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the rate-limiting enzyme of purine salvage into IMP and GMP. Inhibition of de novo guanylate synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells upregulated HGPRT expression and hypoxanthine-derived guanylate salvage but maintained high levels of guanine-derived salvage. Exogenous guanine supplementation decreased radiosensitization in cells treated with combination RT and de novo purine synthesis inhibition. Silencing HGPRT combined with RT markedly suppressed DMG-H3K27M tumor growth in vivo.
Our results indicate that DMG-H3K27M cells rely on highly active purine synthesis, both from the de novo and salvage synthesis pathways. However, highly active salvage of free purine bases into mature guanylates can bypass inhibition of the de novo synthetic pathway. We conclude that inhibiting purine salvage may be a promising strategy to overcome treatment resistance in DMG-H3K27M tumors.
Abstract Medulloblastoma is the most common malignant brain tumor in children. Therapeutic approaches to medulloblastoma (combination of surgery, radiotherapy, and chemotherapy) have led to ...significant improvements, but these are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed. Genetic mutations leading to the activation of the Hedgehog pathway drive tumorigenesis in ~30% of medulloblastoma. In a yeast two-hybrid proteomic screen, we discovered a novel interaction between GLI1, a key transcription factor for the mediation of Hedgehog signals, and PIN1, a peptidylprolyl cis/trans isomerase that regulates the postphosphorylation fate of its targets. The GLI1/PIN1 interaction was validated by reciprocal pulldowns using epitope-tagged proteins in HEK293T cells as well as by co-immunoprecipiations of the endogenous proteins in a medulloblastoma cell line. Our results support a molecular model in which PIN1 promotes GLI1 protein abundance, thus contributing to the positive regulation of Hedgehog signals. Most importantly, in vivo functional analyses of Pin1 in the GFAP-tTA;TRE-SmoA1 mouse model of Hedgehog-driven medulloblastoma demonstrate that the loss of Pin1 impairs tumor development and dramatically increases survival. In summary, the discovery of the GLI1/PIN1 interaction uncovers PIN1 as a novel therapeutic target in Hedgehog-driven medulloblastoma tumorigenesis.
Prion diseases are disorders affecting the central nervous system caused by alterations in the conformation of the cellular prion protein. They can be sporadic, hereditary, or acquired and usually ...present with myoclonus and rapidly progressive dementia in human patients. This article discusses the epidemiology, pathogenesis, diagnosis, and laboratory testing of prion diseases with a primary focus on Creutzfeldt-Jakob disease.
Epigenetic modifications including altered DNA methylation and histone posttranslational modifications (PTM) are central to the biology of several cancers. These modifications can regulate DNA ...accessibility and consequently, gene expression. In this issue, Wojcik and colleagues explore epigenetic drivers of malignant peripheral nerve sheath tumors (MPNST) harboring loss-of-function polycomb-repressive complex 2 mutations. They demonstrate alterations in specific histone PTMs and a global increase in DNA methylation. Notably, epigenetic alterations related with aberrant upregulation of proteins involved in immune evasion, which informed identification of potential therapeutic vulnerabilities. This study helps understand the complex biology of MPNSTs and may enable future therapeutic development.
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