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Histone H3.3G34-mutant interneuron progenitors Co-opt PDGFRA for gliomagenesis

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 stron...

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Hauptverfasser: Chen, Carol C. L. (VerfasserIn) , Deshmukh, Shriya (VerfasserIn) , Jessa, Selin (VerfasserIn) , Hadjadj, Djihad (VerfasserIn) , Lisi, Véronique (VerfasserIn) , Andrade, Augusto Faria (VerfasserIn) , Faury, Damien (VerfasserIn) , Jawhar, Wajih (VerfasserIn) , Dali, Rola (VerfasserIn) , Suzuki, Hiromichi (VerfasserIn) , Pathania, Manav (VerfasserIn) , A, Deli (VerfasserIn) , Dubois, Frank (VerfasserIn) , Woodward, Eleanor (VerfasserIn) , Hébert, Steven (VerfasserIn) , Coutelier, Marie (VerfasserIn) , Karamchandani, Jason (VerfasserIn) , Albrecht, Steffen (VerfasserIn) , Brandner, Sebastian (VerfasserIn) , De Jay, Nicolas (VerfasserIn) , Gayden, Tenzin (VerfasserIn) , Bajic, Andrea (VerfasserIn) , Harutyunyan, Ashot S. (VerfasserIn) , Marchione, Dylan M. (VerfasserIn) , Mikael, Leonie G. (VerfasserIn) , Juretic, Nikoleta (VerfasserIn) , Zeinieh, Michele (VerfasserIn) , Russo, Caterina (VerfasserIn) , Maestro, Nicola (VerfasserIn) , Bassenden, Angelia V. (VerfasserIn) , Hauser, Peter (VerfasserIn) , Virga, József (VerfasserIn) , Bognar, Laszlo (VerfasserIn) , Klekner, Almos (VerfasserIn) , Zapotocky, Michal (VerfasserIn) , Vicha, Ales (VerfasserIn) , Krskova, Lenka (VerfasserIn) , Vanova, Katerina (VerfasserIn) , Zamecnik, Josef (VerfasserIn) , Sumerauer, David (VerfasserIn) , Ekert, Paul G. (VerfasserIn) , Ziegler, David S. (VerfasserIn) , Ellezam, Benjamin (VerfasserIn) , Filbin, Mariella G. (VerfasserIn) , Blanchette, Mathieu (VerfasserIn) , Hansford, Jordan R. (VerfasserIn) , Khuong-Quang, Dong-Anh (VerfasserIn) , Berghuis, Albert M. (VerfasserIn) , Weil, Alexander G. (VerfasserIn) , Garcia, Benjamin A. (VerfasserIn) , Garzia, Livia (VerfasserIn) , Mack, Stephen C. (VerfasserIn) , Beroukhim, Rameen (VerfasserIn) , Ligon, Keith L. (VerfasserIn) , Taylor, Michael D. (VerfasserIn) , Bandopadhayay, Pratiti (VerfasserIn) , Kramm, Christoph (VerfasserIn) , Pfister, Stefan (VerfasserIn) , Korshunov, Andrey (VerfasserIn) , Sturm, Dominik (VerfasserIn) , Jones, David T. W. (VerfasserIn) , Salomoni, Paolo (VerfasserIn) , Kleinman, Claudia L. (VerfasserIn) , Jabado, Nada (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: November 30, 2020
In: Cell
Year: 2020, Jahrgang: 183, Heft: 6
ISSN:1097-4172
DOI:10.1016/j.cell.2020.11.012
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.cell.2020.11.012
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0092867420315294
Volltext
Verfasserangaben:Carol C.L. Chen, Shriya Deshmukh, Selin Jessa, Djihad Hadjadj, Véronique Lisi, Augusto Faria Andrade, Damien Faury, Wajih Jawhar, Rola Dali, Hiromichi Suzuki, Manav Pathania, Deli A, Frank Dubois, Eleanor Woodward, Steven Hébert, Marie Coutelier, Jason Karamchandani, Steffen Albrecht, Sebastian Brandner, Nicolas De Jay, Tenzin Gayden, Andrea Bajic, Ashot S. Harutyunyan, Dylan M. Marchione, Leonie G. Mikael, Nikoleta Juretic, Michele Zeinieh, Caterina Russo, Nicola Maestro, Angelia V. Bassenden, Peter Hauser, József Virga, Laszlo Bognar, Almos Klekner, Michal Zapotocky, Ales Vicha, Lenka Krskova, Katerina Vanova, Josef Zamecnik, David Sumerauer, Paul G. Ekert, David S. Ziegler, Benjamin Ellezam, Mariella G. Filbin, Mathieu Blanchette, Jordan R. Hansford, Dong-Anh Khuong-Quang, Albert M. Berghuis, Alexander G. Weil, Benjamin A. Garcia, Livia Garzia, Stephen C. Mack, Rameen Beroukhim, Keith L. Ligon, Michael D. Taylor, Pratiti Bandopadhayay, Christoph Kramm, Stefan M. Pfister, Andrey Korshunov, Dominik Sturm, David T.W. Jones, Paolo Salomoni, Claudia L. Kleinman, and Nada Jabado

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520 |a 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. 
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650 4 |a single-cell transcriptome 
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