GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant
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.
Authors
- Tara Barron (ORCID: https://orcid.org/0000-0003-3120-0956)
- Carl Koschmann (ORCID: https://orcid.org/0000-0002-0825-7615)
- Mariella G. Filbin (ORCID: https://orcid.org/0000-0002-2613-8126)
- Emelie Braun (ORCID: https://orcid.org/0000-0002-4485-6308)
- Sanda Alexandrescu (ORCID: https://orcid.org/0000-0001-9246-4184)
- Angela Mastronuzzi (ORCID: https://orcid.org/0000-0002-4408-2373)
- Kristina A. Cole (ORCID: https://orcid.org/0000-0003-0064-2882)
- Cristina Bleil (ORCID: https://orcid.org/0000-0002-3845-5831)
- Rodrigo T. Cartaxo (ORCID: https://orcid.org/0009-0001-2011-5695)
- Maria Vinci
- Keith L. Ligon (ORCID: https://orcid.org/0000-0002-7733-600X)
- Ilon Liu (ORCID: https://orcid.org/0000-0002-6186-3630)
- Darren Hargrave (ORCID: https://orcid.org/0000-0001-8219-9807)
- Angela J. Waanders (ORCID: https://orcid.org/0000-0002-0571-2889)
- Yura Grabovska (ORCID: https://orcid.org/0000-0003-3419-2234)
- McKenzie Shaw (ORCID: https://orcid.org/0000-0003-3734-5312)
- Rebecca D. Hodge (ORCID: https://orcid.org/0000-0002-5784-9668)
- Gustavo Alencastro Veiga Cruzeiro (ORCID: https://orcid.org/0000-0002-0005-3984)
- Irene Slavc (ORCID: https://orcid.org/0000-0002-9419-6790)
- Michelle Monje (ORCID: https://orcid.org/0000-0002-3547-237X)
- Hafsa M. Mire (ORCID: https://orcid.org/0000-0001-9293-2953)
- Fernando Carceller (ORCID: https://orcid.org/0000-0003-3094-3758)
- Sibylle Madlener (ORCID: https://orcid.org/0000-0001-7099-9997)
- Chris Jones (ORCID: https://orcid.org/0000-0001-8118-2296)
- Valeria Molinari
- Johannes Gojo (ORCID: https://orcid.org/0000-0002-8113-3416)
- Alexander Beck (ORCID: https://orcid.org/0000-0001-8641-7832)
- Kimberly Siletti (ORCID: https://orcid.org/0000-0001-7620-8973)
- Alan Mackay
- Jenna LaBelle (ORCID: https://orcid.org/0000-0003-3843-320X)
- Bernhard Englinger (ORCID: https://orcid.org/0000-0002-9701-2600)
- Marta Pérez‐Somarriba (ORCID: https://orcid.org/0000-0001-5491-4092)
- Sara Temelso (ORCID: https://orcid.org/0000-0001-6017-8503)
- Olivia A. Hack (ORCID: https://orcid.org/0000-0003-3962-1560)
- Samantha E. Hoffman (ORCID: https://orcid.org/0000-0002-6752-172X)
- Sameer Agnihotri (ORCID: https://orcid.org/0000-0001-6584-3795)
- Andrezza Nascimento (ORCID: https://orcid.org/0000-0002-0629-7402)
- Florence I. Raynaud (ORCID: https://orcid.org/0000-0003-0957-6279)
- Christian Dorfer (ORCID: https://orcid.org/0000-0002-1843-7732)
- Ruth Ruddle (ORCID: https://orcid.org/0000-0003-0025-8872)
- Giulia Pericoli (ORCID: https://orcid.org/0000-0002-1177-9545)
- Jacob S Rozowsky (ORCID: https://orcid.org/0000-0003-1101-3168)
- Michael A. Quezada (ORCID: https://orcid.org/0000-0001-7307-5204)
- David D. Eisenstat (ORCID: https://orcid.org/0000-0002-5976-0798)
- Rene Geyeregger
- Ulrich Schüller (ORCID: https://orcid.org/0000-0002-8731-1121)
- Lijuan Hu (ORCID: https://orcid.org/0000-0003-1869-0372)
- Gerda Ricken (ORCID: https://orcid.org/0000-0003-0388-7965)
- Quang‐Dé Nguyen (ORCID: https://orcid.org/0000-0002-9043-4413)
- Rebecca F. Rogers (ORCID: https://orcid.org/0000-0002-9240-2677)
- Murry Morrow
- Alicia-Christina Baumgartner
- Eshini Panditharatna (ORCID: https://orcid.org/0000-0002-4530-7298)
- Sina Neyazi (ORCID: https://orcid.org/0000-0002-9861-2325)
- Christine Haberler (ORCID: https://orcid.org/0000-0003-1016-0545)
- Miri Danan-Gotthold (ORCID: https://orcid.org/0000-0002-6819-6308)
- Ed S. Lein (ORCID: https://orcid.org/0000-0001-9012-6552)
- Amy Cameron (ORCID: https://orcid.org/0000-0003-2747-8365)
- Sten Linnarsson (ORCID: https://orcid.org/0000-0002-3491-3444)
- Benison Lau
- Christopher Rota (ORCID: https://orcid.org/0000-0003-1790-958X)
- Lisa Mayr (ORCID: https://orcid.org/0000-0002-6841-0749)
- Ángel M. Carcaboso (ORCID: https://orcid.org/0000-0002-8485-426X)
- Erik Sundström (ORCID: https://orcid.org/0000-0003-2931-8015)
- Jiang Li (ORCID: https://orcid.org/0000-0002-9791-2553)
- Andrew King (ORCID: https://orcid.org/0000-0002-4545-6808)
- Sophia Castellani
- Santhosh Uphadhyaya
- Rebecca Haase
- Lynn Bjerke
- Simon Stapleton
Institutions
- Broad Institute (US)
- Boston Children's Hospital (US)
- Lurie Children's Hospital (US)
- Hospital Sant Joan de Déu Barcelona (ES)
- Allen Institute for Brain Science (US)
- Royal Marsden NHS Foundation Trust (GB)
- Children's Hospital of Philadelphia (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Institute of Cancer Research (GB)
- Universität Hamburg (DE)
- The University of Melbourne (AU)
- University of Michigan (US)
- Great Ormond Street Hospital (GB)
- Karolinska Institutet (SE)
- Humboldt-Universität zu Berlin (DE)
- Comprehensive Cancer Center Vienna (AT)
- University Medical Center Hamburg-Eppendorf (DE)
- King's College Hospital NHS Foundation Trust (GB)
- St George's Hospital (GB)
- Dana-Farber Cancer Institute (US)
- Cancer Research Institute of the Slovak Academy of Sciences (SK)
- Royal Marsden Hospital (GB)
- Bambino Gesù Children's Hospital (IT)
- Children's Hospital of Pittsburgh (US)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Allen Institute (US)
- Murdoch Children's Research Institute (AU)
- King's College Hospital (GB)
- Institute of Neurobiology (BG)
- Dana-Farber Brigham Cancer Center (US)
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US)
- Imaging Center (US)
- University College London (GB)
- Community College of Rhode Island (US)
- Medical University of Vienna (AT)
- Charité - Universitätsmedizin Berlin (DE)
- Ludwig-Maximilians-Universität München (DE)
- Stanford University (US)
Publication Details
- Journal
- Cancer Cell
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.ccell.2024.08.006
- Citations
- 45
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 19.71