BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Author:

Panditharatna Eshini12ORCID,Marques Joana G.12ORCID,Wang Tingjian34ORCID,Trissal Maria C.12ORCID,Liu Ilon12ORCID,Jiang Li12ORCID,Beck Alexander5ORCID,Groves Andrew12ORCID,Dharia Neekesh V.12ORCID,Li Deyao34ORCID,Hoffman Samantha E.12ORCID,Kugener Guillaume2ORCID,Shaw McKenzie L.1ORCID,Mire Hafsa M.12ORCID,Hack Olivia A.1ORCID,Dempster Joshua M.2ORCID,Lareau Caleb26ORCID,Dai Lingling34ORCID,Sigua Logan H.34ORCID,Quezada Michael A.7ORCID,Stanton Ann-Catherine J.89ORCID,Wyatt Meghan2ORCID,Kalani Zohra2ORCID,Goodale Amy2ORCID,Vazquez Francisca2ORCID,Piccioni Federica210ORCID,Doench John G.2ORCID,Root David E.2ORCID,Anastas Jamie N.1112ORCID,Jones Kristen L.13ORCID,Conway Amy Saur1ORCID,Stopka Sylwia1415ORCID,Regan Michael S.1415ORCID,Liang Yu34ORCID,Seo Hyuk-Soo3416ORCID,Song Kijun3ORCID,Bashyal Puspalata34ORCID,Jerome William P.1ORCID,Mathewson Nathan D.171819ORCID,Dhe-Paganon Sirano3416ORCID,Suvà Mario L.2021ORCID,Carcaboso Angel M.22ORCID,Lavarino Cinzia22ORCID,Mora Jaume22ORCID,Nguyen Quang-De13,Ligon Keith L.12232425ORCID,Shi Yang1126ORCID,Agnihotri Sameer89ORCID,Agar Nathalie Y.R.341415ORCID,Stegmaier Kimberly12ORCID,Stiles Charles D.34ORCID,Monje Michelle27ORCID,Golub Todd R.12ORCID,Qi Jun34ORCID,Filbin Mariella G.12ORCID

Affiliation:

1. 1Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.

2. 2Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.

3. 3Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.

4. 4Department of Medicine, Harvard Medical School, Boston, Massachusetts.

5. 5Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany.

6. 6Department of Pathology, Stanford University, Stanford, California.

7. 7Department of Neurology, Stanford University School of Medicine, Stanford, California.

8. 8Department of Neurosurgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

9. 9Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

10. 10Merck Research Laboratories, Cambridge, Massachusetts.

11. 11Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.

12. 12Department of Neurosurgery and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.

13. 13Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

14. 14Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

15. 15Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

16. 16Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.

17. 17Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

18. 18Department of Microbiology and Immunobiology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

19. 19Department of Neurology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

20. 20Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

21. 21Klarman Cell Observatory, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.

22. 22Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.

23. 23Department of Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.

24. 24Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.

25. 25Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.

26. 26Ludwig Institute for Cancer Research, Oxford Branch, Oxford University, Oxford, United Kingdom.

27. 27Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California.

Abstract

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. 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.

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology

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