BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
02 12 2022
02 12 2022
Historique:
received:
08
11
2021
revised:
03
08
2022
accepted:
15
09
2022
pubmed:
29
10
2022
medline:
6
12
2022
entrez:
28
10
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36305736
pii: 710072
doi: 10.1158/2159-8290.CD-21-1491
pmc: PMC9716260
doi:
Substances chimiques
Transcription Factors
0
SMARCA4 protein, human
EC 3.6.1.-
DNA Helicases
EC 3.6.4.-
Nuclear Proteins
0
Types de publication
Editorial
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Comment
Langues
eng
Sous-ensembles de citation
IM
Pagination
2880-2905Subventions
Organisme : NIBIB NIH HHS
ID : T32 EB025823
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA210104
Pays : United States
Organisme : NIBIB NIH HHS
ID : P41 EB015898
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007753
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA210030
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM144273
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA210180
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA136432
Pays : United States
Organisme : NIBIB NIH HHS
ID : P41 EB028741
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentOn
Type : CommentIn
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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