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

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; Nada Jabado

doi:10.1016/j.cell.2020.11.012

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

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 JayTenzin 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, Nada Jabado

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112 Scopus citations

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.

Original language	English
Pages (from-to)	1617-1633.e22
Journal	Cell
Volume	183
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2020.11.012
State	Published - Dec 10 2020

Keywords

GSX2
H3.3 G34R/V
PDGFRA
cell-of-origin
chromatin conformation
gliomas
interneuron progenitors
oncohistones
pediatric cancer
single-cell transcriptome

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10.1016/j.cell.2020.11.012

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Chen, C. C. L., Deshmukh, S., Jessa, S., Hadjadj, D., Lisi, V., Andrade, A. F., Faury, D., Jawhar, W., Dali, R., Suzuki, H., Pathania, M., A, D., Dubois, F., Woodward, E., Hébert, S., Coutelier, M., Karamchandani, J., Albrecht, S., Brandner, S., ... Jabado, N. (2020). Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis. Cell, 183(6), 1617-1633.e22. https://doi.org/10.1016/j.cell.2020.11.012

@article{d50742399c7b4808a0841c6f8a265f23,

title = "Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis",

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.",

keywords = "GSX2, H3.3 G34R/V, PDGFRA, cell-of-origin, chromatin conformation, gliomas, interneuron progenitors, oncohistones, pediatric cancer, single-cell transcriptome",

author = "Chen, {Carol C.L.} and Shriya Deshmukh and Selin Jessa and Djihad Hadjadj and V{\'e}ronique Lisi and Andrade, {Augusto Faria} and Damien Faury and Wajih Jawhar and Rola Dali and Hiromichi Suzuki and Manav Pathania and Deli A and Frank Dubois and Eleanor Woodward and Steven H{\'e}bert and Marie Coutelier and Jason Karamchandani and Steffen Albrecht and Sebastian Brandner and {De Jay}, Nicolas and Tenzin Gayden and Andrea Bajic and Harutyunyan, {Ashot S.} and Marchione, {Dylan M.} and Mikael, {Leonie G.} and Nikoleta Juretic and Michele Zeinieh and Caterina Russo and Nicola Maestro and Bassenden, {Angelia V.} and Peter Hauser and J{\'o}zsef Virga and Laszlo Bognar and Almos Klekner and Michal Zapotocky and Ales Vicha and Lenka Krskova and Katerina Vanova and Josef Zamecnik and David Sumerauer and Ekert, {Paul G.} and Ziegler, {David S.} and Benjamin Ellezam and Filbin, {Mariella G.} and Mathieu Blanchette and Hansford, {Jordan R.} and Khuong-Quang, {Dong Anh} and Berghuis, {Albert M.} and Weil, {Alexander G.} and Garcia, {Benjamin A.} and Livia Garzia and Mack, {Stephen C.} and Rameen Beroukhim and Ligon, {Keith L.} and Taylor, {Michael D.} and Pratiti Bandopadhayay and Christoph Kramm and Pfister, {Stefan M.} and Andrey Korshunov and Dominik Sturm and Jones, {David T.W.} and Paolo Salomoni and Kleinman, {Claudia L.} and Nada Jabado",

note = "Publisher Copyright: {\textcopyright} 2020",

year = "2020",

month = dec,

day = "10",

doi = "10.1016/j.cell.2020.11.012",

language = "English",

volume = "183",

pages = "1617--1633.e22",

journal = "Cell",

issn = "0092-8674",

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Chen, CCL, Deshmukh, S, Jessa, S, Hadjadj, D, Lisi, V, Andrade, AF, Faury, D, Jawhar, W, Dali, R, Suzuki, H, Pathania, M, A, D, Dubois, F, Woodward, E, Hébert, S, Coutelier, M, Karamchandani, J, Albrecht, S, Brandner, S, De Jay, N, Gayden, T, Bajic, A, Harutyunyan, AS, Marchione, DM, Mikael, LG, Juretic, N, Zeinieh, M, Russo, C, Maestro, N, Bassenden, AV, Hauser, P, Virga, J, Bognar, L, Klekner, A, Zapotocky, M, Vicha, A, Krskova, L, Vanova, K, Zamecnik, J, Sumerauer, D, Ekert, PG, Ziegler, DS, Ellezam, B, Filbin, MG, Blanchette, M, Hansford, JR, Khuong-Quang, DA, Berghuis, AM, Weil, AG, Garcia, BA, Garzia, L, Mack, SC, Beroukhim, R, Ligon, KL, Taylor, MD, Bandopadhayay, P, Kramm, C, Pfister, SM, Korshunov, A, Sturm, D, Jones, DTW, Salomoni, P, Kleinman, CL & Jabado, N 2020, 'Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis', Cell, vol. 183, no. 6, pp. 1617-1633.e22. https://doi.org/10.1016/j.cell.2020.11.012

TY - JOUR

T1 - Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis

AU - Chen, Carol C.L.

AU - Deshmukh, Shriya

AU - Jessa, Selin

AU - Hadjadj, Djihad

AU - Lisi, Véronique

AU - Andrade, Augusto Faria

AU - Faury, Damien

AU - Jawhar, Wajih

AU - Dali, Rola

AU - Suzuki, Hiromichi

AU - Pathania, Manav

AU - A, Deli

AU - Dubois, Frank

AU - Woodward, Eleanor

AU - Hébert, Steven

AU - Coutelier, Marie

AU - Karamchandani, Jason

AU - Albrecht, Steffen

AU - Brandner, Sebastian

AU - De Jay, Nicolas

AU - Gayden, Tenzin

AU - Bajic, Andrea

AU - Harutyunyan, Ashot S.

AU - Marchione, Dylan M.

AU - Mikael, Leonie G.

AU - Juretic, Nikoleta

AU - Zeinieh, Michele

AU - Russo, Caterina

AU - Maestro, Nicola

AU - Bassenden, Angelia V.

AU - Hauser, Peter

AU - Virga, József

AU - Bognar, Laszlo

AU - Klekner, Almos

AU - Zapotocky, Michal

AU - Vicha, Ales

AU - Krskova, Lenka

AU - Vanova, Katerina

AU - Zamecnik, Josef

AU - Sumerauer, David

AU - Ekert, Paul G.

AU - Ziegler, David S.

AU - Ellezam, Benjamin

AU - Filbin, Mariella G.

AU - Blanchette, Mathieu

AU - Hansford, Jordan R.

AU - Khuong-Quang, Dong Anh

AU - Berghuis, Albert M.

AU - Weil, Alexander G.

AU - Garcia, Benjamin A.

AU - Garzia, Livia

AU - Mack, Stephen C.

AU - Beroukhim, Rameen

AU - Ligon, Keith L.

AU - Taylor, Michael D.

AU - Bandopadhayay, Pratiti

AU - Kramm, Christoph

AU - Pfister, Stefan M.

AU - Korshunov, Andrey

AU - Sturm, Dominik

AU - Jones, David T.W.

AU - Salomoni, Paolo

AU - Kleinman, Claudia L.

AU - Jabado, Nada

PY - 2020/12/10

Y1 - 2020/12/10

N2 - 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.

AB - 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.

KW - GSX2

KW - H3.3 G34R/V

KW - PDGFRA

KW - cell-of-origin

KW - chromatin conformation

KW - gliomas

KW - interneuron progenitors

KW - oncohistones

KW - pediatric cancer

KW - single-cell transcriptome

UR - http://www.scopus.com/inward/record.url?scp=85097741684&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2020.11.012

DO - 10.1016/j.cell.2020.11.012

M3 - Article

C2 - 33259802

AN - SCOPUS:85097741684

SN - 0092-8674

VL - 183

SP - 1617-1633.e22

JO - Cell

JF - Cell

IS - 6

ER -

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

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Keywords

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