HGG-06. EARLY GABAERGIC NEURONAL LINEAGE DEFINES DEPENDENCIES IN HISTONE H3 G34R/V GLIOMA
| Autor: | Sameer Agnihotri, Joshua M. Dempster, Li Jiang, Erik Sundstroem, Johannes Gojo, Olivia A Hack, Christine Haberler, Kristina A. Cole, Miri Danan-Gotthold, McKenzie Shaw, Ed S. Lein, Yura Grabovska, Gustavo Alencastro Veiga Cruzeiro, Samantha E Hoffman, Ilon Liu, Christian Dorfer, Sanda Alexandrescu, Sara Temelso, Bernhard Englinger, Valeria Molinari, Christopher Rota, Lynn Bjerke, Chris Jones, Sten Linnarsson, René Geyeregger, Lisa Mayr, Irene Slavc, Cristina Bleil, Hafsa M Mire, Angela Waanders, Tara Barron, Angela Mastronuzzi, Gerda Ricken, Eshini Panditharatna, Kimberly Siletti, Lijuan Hu, Alan L. Mackay, Simon R. Stapleton, Michelle Monje, Emelie Braun, Michael Quezada, Mariella G. Filbin, David D Eisenstat, Sibylle Madlener, Maria Vinci, Rebecca Hodge, Fernando Carceller, Angel M. Carcaboso, Darren Hargrave, Rebecca Rogers |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Neuro-Oncology |
| ISSN: | 1523-5866 1522-8517 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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