Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis

Cell. 2020 Dec 10;183(6):1617-1633.e22. doi: 10.1016/j.cell.2020.11.012. | PubMed

Carol C L Chen¹, Shriya Deshmukh², Selin Jessa³, Djihad Hadjadj¹, Véronique Lisi¹, Augusto Faria Andrade¹, Damien Faury⁴, Wajih Jawhar¹, Rola Dali⁵, Hiromichi Suzuki⁶, Manav Pathania⁷, Deli A⁸, Frank Dubois⁹, Eleanor Woodward⁹, Steven Hébert¹⁰, Marie Coutelier¹⁰, Jason Karamchandani¹¹, Steffen Albrecht¹², Sebastian Brandner¹³, Nicolas De Jay¹⁰, Tenzin Gayden¹, Andrea Bajic¹, Ashot S Harutyunyan⁴, Dylan M Marchione¹⁴, Leonie G Mikael⁴, Nikoleta Juretic⁴, Michele Zeinieh¹, Caterina Russo⁴, Nicola Maestro¹⁵, Angelia V Bassenden¹⁶, Peter Hauser¹⁷, József Virga¹⁸, Laszlo Bognar¹⁹, Almos Klekner¹⁹, Michal Zapotocky²⁰, Ales Vicha²⁰, Lenka Krskova²¹, Katerina Vanova²⁰, Josef Zamecnik²¹, David Sumerauer²⁰, Paul G Ekert²², David S Ziegler²³, Benjamin Ellezam²⁴, Mariella G Filbin²⁵, Mathieu Blanchette²⁶, Jordan R Hansford²², Dong-Anh Khuong-Quang²⁷, Albert M Berghuis¹⁶, Alexander G Weil²⁸, Benjamin A Garcia¹⁴, Livia Garzia²⁹, Stephen C Mack³⁰, Rameen Beroukhim³¹, Keith L Ligon³², Michael D Taylor⁶, Pratiti Bandopadhayay³³, Christoph Kramm³⁴, Stefan M Pfister³⁵, Andrey Korshunov³⁶, Dominik Sturm³⁷, David T W Jones³⁸, Paolo Salomoni³⁹, Claudia L Kleinman⁴⁰, Nada Jabado⁴¹

1. Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
2. Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
3. Quantitative Life Sciences, McGill University, Montreal, QC H3A 2A7, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
4. Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
5. Canadian Centre for Computational Genomics, McGill University, Montreal, QC H3A 0E9, Canada.
6. Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
7. Department of Oncology and The Milner Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; CRUK Children's Brain Tumour Centre of Excellence, University of Cambridge, Cambridge CB2 0RE, UK.
8. Nuclear Function in CNS Pathophysiology, German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany.
9. Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
10. Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
11. Department of Pathology, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
12. Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
13. UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
14. Department of Biochemistry and Biophysics and Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6073, USA.
15. Department of Oncology and The Milner Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
16. Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
17. Second Department of Paediatrics, Semmelweis University, Budapest 1094, Hungary.
18. Department of Neurosurgery, University of Debrecen, Debrecen 4032, Hungary; Department of Oncology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.
19. Department of Neurosurgery, University of Debrecen, Debrecen 4032, Hungary.
20. Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague 150 06, Czech Republic.
21. Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague 150 06, Czech Republic.
22. Children's Cancer Center, The Royal Children's Hospital; Murdoch Children's Research Institute; Department of Pediatrics, University of Melbourne, Parkville, VIC 3052, Australia.
23. Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Sydney, Kensington, NSW 2052, Australia.
24. Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, QC H3T 1C5, Canada.
25. Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA.
26. School of Computer Science, McGill University, Montreal, QC H3A 2A7, Canada.
27. Children's Cancer Center, The Royal Children's Hospital; and Murdoch Children's Research Institute; Parkville, VIC 3052, Australia.
28. Department of Pediatric Neurosurgery, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, QC H3T 1C5, Canada.
29. Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Division of Orthopedic Surgery, Faculty of Surgery, McGill University, Montreal, QC H3G 1A4, Canada.
30. Department of Pediatrics, Division of Hematology and Oncology, Texas Children's Cancer and Hematology Centers, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
31. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215-5450, USA; Broad Institute of MIT and Harvard, Boston, MA 02142, USA.
32. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215-5450, USA; Department of Pathology, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, and Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
33. Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215-5450, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
34. Division of Pediatric Hematology and Oncology, University Medical Center Goettingen, Goettingen 37075, Germany.
35. Hopp Children's Cancer Center Heidelberg (KiTZ) and Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg 69120, Germany; Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany.
36. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg 69120, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
37. Division of Pediatric Hematology and Oncology, University Medical Center Goettingen, Goettingen 37075, Germany; Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
38. Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg 69120, Germany.
39. Department of Oncology and The Milner Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Nuclear Function in CNS Pathophysiology, German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany.
40. Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada. Electronic address: claudia.kleinman@mcgill.ca.
41. Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada; Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada. Electronic address: nada.jabado@mcgill.ca.

Abstract

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.

Presented By Carol Chen, Shriya Deshmukh & Selin Jessa