GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant.

Autor:	Liu I; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Neurology with Experimental Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin und Humboldt-Universität zu Berlin, 10117 Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Digital Clinician Scientist Program, 10117 Berlin, Germany., Alencastro Veiga Cruzeiro G; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Bjerke L; Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey SM2 5 NG, UK., Rogers RF; Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey SM2 5 NG, UK., Grabovska Y; Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey SM2 5 NG, UK., Beck A; Center for Neuropathology, Ludwig-Maximilians-University, 81377 Munich, Germany., Mackay A; Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey SM2 5 NG, UK., Barron T; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA., Hack OA; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Quezada MA; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA., Molinari V; Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey SM2 5 NG, UK., Shaw ML; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Perez-Somarriba M; Children & Young People's Unit, Royal Marsden Hospital NHS Trust, Sutton, Surrey SM2 5 NG, UK., Temelso S; Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey SM2 5 NG, UK., Raynaud F; Division of Cancer Therapeutics, The Institute of Cancer Research, London SW7 3RK, UK., Ruddle R; Division of Cancer Therapeutics, The Institute of Cancer Research, London SW7 3RK, UK., Panditharatna E; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Englinger B; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Mire HM; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Jiang L; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Nascimento A; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., LaBelle J; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Haase R; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Rozowsky J; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Neyazi S; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Baumgartner AC; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Castellani S; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Hoffman SE; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Cameron A; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Morrow M; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Nguyen QD; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Pericoli G; Department of Onco-haematology, Gene and Cell Therapy, Bambino Gesù Children's Hospital-IRCCS, 00165 Rome, Italy., Madlener S; Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Mayr L; Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Dorfer C; Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria., Geyeregger R; Clinical Cell Biology, Children's Cancer Research Institute (CCRI), Vienna 1090, Austria., Rota C; Department of Neurobiology, Harvard Medical School, Boston, MA 02215, USA., Ricken G; Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna 1090, Austria., Ligon KL; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA., Alexandrescu S; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA., Cartaxo RT; Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA., Lau B; Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA., Uphadhyaya S; Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA., Koschmann C; Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA., Braun E; Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden., Danan-Gotthold M; Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden., Hu L; Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden., Siletti K; Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden., Sundström E; Division of Neurodegeneration, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, 17177 Stockholm, Sweden., Hodge R; Allen Institute for Brain Science, Seattle, WA 98109, USA., Lein E; Allen Institute for Brain Science, Seattle, WA 98109, USA., Agnihotri S; Departments of Neurosurgery and Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA., Eisenstat DD; Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia., Stapleton S; Department of Neurosurgery, St George's Hospital NHS Trust, London SW17 0QT, UK., King A; Department of Neuropathology, King's College Hospital NHS Trust, London SE5 9RS, UK., Bleil C; Department of Neurosurgery, King's College Hospital NHS Trust, London SE5 9RS, UK., Mastronuzzi A; Department of Onco-haematology, Gene and Cell Therapy, Bambino Gesù Children's Hospital-IRCCS, 00165 Rome, Italy., Cole KA; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Waanders AJ; Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA., Montero Carcaboso A; Laboratory of Molecular Oncology, Hospital Sant Joan de Déu, 08950 Barcelona, Spain., Schüller U; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany., Hargrave D; University College London Great Ormond Street Institute for Child Health, London WC1N 1EH, UK., Vinci M; Department of Onco-haematology, Gene and Cell Therapy, Bambino Gesù Children's Hospital-IRCCS, 00165 Rome, Italy., Carceller F; Children & Young People's Unit, Royal Marsden Hospital NHS Trust, Sutton, Surrey SM2 5 NG, UK; Division of Clinical Studies, The Institute of Cancer Research, London SW7 3RK, UK., Haberler C; Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna 1090, Austria., Slavc I; Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Linnarsson S; Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden., Gojo J; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Monje M; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA, USA., Jones C; Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey SM2 5 NG, UK. Electronic address: chris.jones@icr.ac.uk., Filbin MG; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: mariella.filbin@childrens.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2024 Aug 27. Date of Electronic Publication: 2024 Aug 27.
DOI:	10.1016/j.ccell.2024.08.006
Abstrakt:	Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17 months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target. Competing Interests: Declaration of interests M.G.F. is a consultant for Twentyeight-Seven Therapeutics and Blueprint Medicines. M.M. is an SAB member for Cygnal Therapeutics. K.L.L. is founder and equity holder of Travera Inc. and receives consulting fees from BMS, Integragen, and Rarecyte, and research support from Lilly, BMS, and Amgen. D.H. has acted as an advisor for Novartis in relation to ribociclib. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu