BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma
Por:
Panditharatna E, G Marques J, Wang T, Trissal MC, Liu I, Jiang L, Beck A, Groves A, Dharia NV, Li D, Hoffman SE, Kugener G, Shaw ML, Mire HM, Hack OA, Dempster JM, Lareau C, Dai L, Sigua LH, Quezada MA, Stanton AJ, Wyatt M, Kalani Z, Goodale A, Vazquez F, Piccioni F, Doench JG, Root DE, Anastas JN, Jones KL, Saur Conway A, Stopka S, Regan MS, Liang Y, Seo HS, Song K, Bashyal P, Jerome WP, Mathewson ND, Dhe-Paganon S, Suva ML, Carcaboso AM, Lavarino C, Mora J, Nguyen QD, Ligon KL, Shi Y, Agnihotri S, Agar NYR, Stegmaier K, Stiles CD, Monje M, Golub TR, Qi J and Filbin MG
Publicada:
1 dic 2022
Categoría:
Oncology
Resumen:
Diffuse midline gliomas are uniformly fatal pediatric central nervous system can-cers 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 architec-ture, 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 depend-ent 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 suppres-sion, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that thera-peutic 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 as a novel treatment strategy for pediatric H3K27M glioma.
Filiaciones:
Panditharatna E:
Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, United States
G Marques J:
Children's Clinical University Hospital, Boston, United States
Wang T:
Dana-Farber Cancer Institute, Boston, ma, United States
Trissal MC:
Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, United States
Liu I:
Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, United States
Jiang L:
Dana-Farber Boston Children's Cancer and Blood Disorders Center, United States
Beck A:
Ludwig-Maximilians-Universität München, Munich, Germany
Groves A:
University of Iowa Children's Hospital, Iowa City, Iowa, United States
Dharia NV:
Genentech, Inc., South San Francisco, CA, United States
Li D:
Dana-Farber Cancer Institute, Boston, ma, United States
Hoffman SE:
Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, United States
Kugener G:
Broad Institute of MIT and Harvard, Cambridge, MA, United States
Shaw ML:
Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
Mire HM:
Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, United States
Hack OA:
Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, United States
Dempster JM:
Broad Institute of Harvard and MIT, Cambridge, MA, United States
Lareau C:
Stanford University, Stanford, United States
Dai L:
Dana-Farber Cancer Institute, United States
Sigua LH:
Dana-Farber Cancer Institute, Boston, ma, United States
Quezada MA:
Stanford University, Stanford, United States
Stanton AJ:
University of Pittsburgh, Pittsburgh, PA, United States
Wyatt M:
Broad Institute, United States
Kalani Z:
Broad Institute, United States
Goodale A:
Broad Institute of Harvard and MIT, Cambridge, MA, United States
Vazquez F:
Broad Institute of Harvard and MIT, Cambridge, MA, United States
Piccioni F:
Broad Institute of MIT and Harvard, Cambridge, MA, United States
Doench JG:
Broad Institute of MIT and Harvard, Cambridge, MA, United States
Root DE:
Broad Institute of Harvard and MIT, Cambridge, MA, United States
Anastas JN:
Boston Children's Hospital, United States
Jones KL:
Dana-Farber Cancer Institute, Boston, ma, United States
Saur Conway A:
Dana-Farber Cancer Institute, Boston, ma, United States
Stopka S:
Brigham and Women's Hospital, Boston, United States
Regan MS:
Brigham and Women's Hospital, Boston, MA, United States
Liang Y:
Dana-Farber Cancer Institute, Boston, ma, United States
Seo HS:
Dana-Farber Cancer Institute, Boston, United States
Song K:
Dana-Farber Cancer Institute, Boston, United States
Bashyal P:
Harvard University, Longwood, United States
Jerome WP:
Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, United States
Mathewson ND:
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
Dhe-Paganon S:
Dana-Farber Cancer Institute, Boston, United States
Suva ML:
Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
Carcaboso AM:
Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Lavarino C:
Hospital Sant Joan de Déu, Barcelona, Spain
Mora J:
Hospital Sant Joan de Déu, Barcelona, Catalonia, Spain
Nguyen QD:
Dana-Farber Cancer Institute, Boston, ma, United States
Ligon KL:
Dana-Farber Cancer Institute, Boston, ma, United States
Shi Y:
Boston Children's Hospital, United States
Agnihotri S:
University of Pittsburgh, Pittsburgh, PA, United States
Agar NYR:
Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
Stegmaier K:
Dana-Farber Cancer Institute, Boston, ma, United States
Stiles CD:
Dana-Farber Cancer Institute, Boston, ma, United States
Monje M:
Stanford University, Stanford, CA, United States
Golub TR:
Broad Institute, Camridge, MA, United States
Qi J:
Dana-Farber Cancer Institute, Boston, ma, United States
Filbin MG:
Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, United States
Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany.; Department of Pathology, Stanford Unive
Green Submitted, Bronze
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