BAF complex maintains glioma stem cells in pediatric H3K27M-glioma.

Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers, 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 (OPC)-like state, where genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacological 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 BAF complex has translational potential for children with H3K27M-gliomas.