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Supplementary Table from BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

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posted on 2023-04-04, 00:22 authored by Eshini Panditharatna, Joana G. Marques, Tingjian Wang, Maria C. Trissal, Ilon Liu, Li Jiang, Alexander Beck, Andrew Groves, Neekesh V. Dharia, Deyao Li, Samantha E. Hoffman, Guillaume Kugener, McKenzie L. Shaw, Hafsa M. Mire, Olivia A. Hack, Joshua M. Dempster, Caleb Lareau, Lingling Dai, Logan H. Sigua, Michael A. Quezada, Ann-Catherine J. Stanton, Meghan Wyatt, Zohra Kalani, Amy Goodale, Francisca Vazquez, Federica Piccioni, John G. Doench, David E. Root, Jamie N. Anastas, Kristen L. Jones, Amy Saur Conway, Sylwia Stopka, Michael S. Regan, Yu Liang, Hyuk-Soo Seo, Kijun Song, Puspalata Bashyal, William P. Jerome, Nathan D. Mathewson, Sirano Dhe-Paganon, Mario L. Suvà, Angel M. Carcaboso, Cinzia Lavarino, Jaume Mora, Quang-De Nguyen, Keith L. Ligon, Yang Shi, Sameer Agnihotri, Nathalie Y.R. Agar, Kimberly Stegmaier, Charles D. Stiles, Michelle Monje, Todd R. Golub, Jun Qi, Mariella G. Filbin
Supplementary Table from BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Funding

V Foundation for Cancer Research (VFCR)

Cuming Family Fund for Pediatric Brain Tumor Research

Sajni Fund

Pediatric Brain Tumor Foundation (PBTF)

Musella Foundation For Brain Tumor Research and Information (Musella Foundation)

National Institutes of Health (NIH)

Burroughs Wellcome Fund (BWF)

Sontag Foundation (The Sontag Foundation)

Alex's Lemonade Stand Foundation for Childhood Cancer (ALSF)

Hyundai Hope On Wheels (Hope On Wheels)

Dana-Farber/Harvard Cancer Center (DF/HCC)

Michael Mosier Defeat DIPG Foundation

ChadTough Foundation (Chad Tough Foundation)

SoSo Strong Pediatric Brain Tumor Foundation

Pan-Massachusetts Challenge (PMC)

David Abraham Foundation

Swiss National Science Foundation - Early Postdoc Mobility

Deutsche Forschungsgemeinschaft (DFG)

Ferenc Jolesz National Center for Image Guided Therapy

Dana-Farber Cancer Institute (DFCI)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Ludwig Institute for Cancer Research (LICR)

Michael Mosier Defeat DIPG

Linde Family Foundation

Doris Duke Charitable Foundation (DDCF)

MIT/Mayo Physical Science Oncology Center for Drug Distribution and Drug Efficacy in Brain Tumors

History

ARTICLE ABSTRACT

Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell–like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas. Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1–BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma.See related commentary by Beytagh and Weiss, p. 2730.See related article by Mo et al., p. 2906.This article is highlighted in the In This Issue feature, p. 2711

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