HGG-06. EARLY GABAERGIC NEURONAL LINEAGE DEFINES DEPENDENCIES IN HISTONE H3 G34R/V GLIOMA. (1st June 2021)

• Record Type: Journal Article
• Authors: Liu, Ilon; Bjerke, Lynn; Cruzeiro, Gustavo Alencastro Veiga; Rogers, Rebecca F; Grabovska, Yura; Panditharatna, Eshini; Mackay, Alan; Barron, Tara; Shaw, McKenzie; Hoffman, Samantha E; Hack, Olivia A; Quezada, Michael A; Dempster, Joshua; Temelso, Sara; Englinger, Bernhard; Molinari, Valeria; Mire, Hafsa M; Jiang, Li; Madlener, Sibylle; Mayr, Lisa; Dorfer, Christian; Geyeregger, Rene; Rota, Christopher; Ricken, Gerda; Alexandrescu, Sanda; Braun, Emelie; Danan-Gotthold, Miri; Hu, Lijuan; Siletti, Kimberly; Sundstroem, Erik; Hodge, Rebecca; Lein, Ed; Agnihotri, Sameer; Eisenstat, David D; Carceller, Fernando; Stapleton, Simon; Bleil, Cristina; Mastronuzzi, Angela; Cole, Kristina A; Waanders, Angela J; Carcaboso, Angel Montero; Vinci, Maria; Hargrave, Darren; Haberler, Christine; Gojo, Johannes; Slavc, Irene; Linnarsson, Sten; Monje, Michelle; Jones, Chris; Filbin, Mariella G;
• Is Part Of: Neuro-oncology. Volume 23(2021)Supplement 1
• Page Start: i18
• Page End: i18
• Publication Date: 2021-06-01
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab090.072
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: High-grade gliomas harboring H3 G34R/V mutations exclusively occur in the cerebral hemispheres of adolescents and young adults, suggesting a distinct neurodevelopmental origin. Combining multimodal bulk and single-cell genomics with unbiased genome-scale CRISPR/Cas9 approaches, we here describe a GABAergic interneuron progenitor lineage as the most likely context from which these H3 G34R/V mutations drive gliomagenesis, conferring unique and tumor-selective gene targets essential for glioma cell survival, as validated genetically and pharmacologically. Phenotypically, we demonstrate that while H3 G34R/V glioma cells harbor the neurotransmitter GABA, they are developmentally stalled, and do not induce the neuronal hyperexcitability described in other glioma subtypes. These findings offer a striking counter-example to the prevailing view of glioma origins in glial precursor cells, resulting in distinct cellular, microenvironmental, and therapeutic consequences.