BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma
Abstract
UNLABELLED: 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.
SIGNIFICANCE: 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…
Read the paper
Related studies
- Learning from First-Generation Qualitative Approaches in the IS Discipline: An Evolutionary View and Some Implications for Authors and Evaluators (PART 1/2)
- Commentary on the clinical and preclinical dosage limits of interstitially administered magnetic fluids for therapeutic hyperthermia based on current practice and efficacy models
- Prosthesis: New Technological Opportunities and Innovative Biomedical Devices
- The history and future of neural modeling for cochlear implants
- Ryanodine receptors: waking up from refractoriness
- Novel Transgenic Rabbit Model Sheds Light on the Puzzling Role of Matrix Metalloproteinase-12 in Atherosclerosis
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.