STEM-16. MACROH2A2 REPRESSES AN EPIGENETIC SELF-RENEWAL NETWORK IN GLIOBLASTOMA STEM CELLS

Abstract Glioblastoma is a highly malignant tumour driven by a subset of self-renewing cells termed glioblastoma stem cells. This self-renewal phenotype is largely epigenetically driven, however, the exact epigenetic mechanisms underpinning it are poorly understood. We found that the histone variant...

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Published in:Neuro-oncology (Charlottesville, Va.) Va.), 2022-11, Vol.24 (Supplement_7), p.vii34-vii34
Main Authors: Nikolic, Ana, Bobyn, Anna, Maule, Francesca, Ellestad, Katrina, Paik, Seungil, Marhon, Sajid, Mehdipour, Parinaz, Lun, Xuequng, Johnston, Michael, Gafiuk, Christopher, Zemp, Franz, Shen, Yaoqing, Ninkovic, Nicoletta, Labit, Elodie, Berger, N Daniel, Brownsey, Duncan, Kelly, John, Biernaskie, Jeff, Dirks, Peter, Derksen, Darren, Jones, Steven J M, Senger, Donna L, Chan, Jennifer, Mahoney, Douglas J, de Carvalho, Daniel, Gallo, Marco
Format: Article
Language:English
Subjects:
Cancer Stem Cell
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Summary:Abstract Glioblastoma is a highly malignant tumour driven by a subset of self-renewing cells termed glioblastoma stem cells. This self-renewal phenotype is largely epigenetically driven, however, the exact epigenetic mechanisms underpinning it are poorly understood. We found that the histone variant macroH2A2 is repressed in a subset of glioblastoma tumours, and that this repression is associated with poorer survival. We interrogate the function of macroH2A2 using in vitro and in vivo patient-derived models. We show that macroH2A2 antagonizes self-renewal and expression of NPC and OPC-like markers, and rewires accessible chromatin by maintaining accessibility at a subset of enhancer elements. We identify small molecules that can upregulate macroH2A2 expression, and find that treatment with a small molecule reduces self-renewal, induces interferon sensitive genes, and a viral mimicry response, effects which are abolished by macroH2A2 knockdown. In summary, we identify macroH2A2 as a repressor of self-renewal in glioblastoma and suggest it may be a novel biomarker and potential marker of therapeutic susceptibility.
ISSN:1522-8517
1523-5866
DOI:10.1093/neuonc/noac209.133