A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M

Yusuke Tomita; Yosuke Shimazu; Agila Somasundaram; Yoshihiro Tanaka; Nozomu Takata; Yukitomo Ishi; Samantha Gadd; Rintaro Hashizume; Angelo Angione; Gonzalo Pinero; Dolores Hambardzumyan; Daniel J. Brat; Christine M. Hoeman; Oren J. Becher

doi:10.1002/glia.24189

A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M

Yusuke Tomita, Yosuke Shimazu, Agila Somasundaram, Yoshihiro Tanaka, Nozomu Takata, Yukitomo Ishi, Samantha Gadd, Rintaro Hashizume, Angelo Angione, Gonzalo Pinero, Dolores Hambardzumyan, Daniel J. Brat, Christine M. Hoeman, Oren J. Becher^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A or PDGF-B overexpression, along with p53 deletion, resulted in gliomas in both models. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, both in PDGF-A and PDGF-B-driven models, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. RNA-sequencing analysis revealed that the differentially expressed genes in H3.3K27M tumors were non-overlapping between Olig2;PDGF-B, Olig2;PDGF-A, and Nestin;PDGF-A models. GSEA analysis of PDGFA tumors confirmed that the transcriptomal effects of H3.3K27M are cell-of-origin dependent with H3.3K27M promoting epithelial-to-mesenchymal transition (EMT) and angiogenesis when Olig2 marks the cell-of-origin and inhibiting EMT and angiogenesis when Nestin marks the cell-of-origin. We did observe some overlap with H3.3K27M promoting negative enrichment of TNFA_Signaling_Via_NFKB in both models. Our study suggests that the tumorigenic effects of H3.3K27M are cell-of-origin dependent, with H3.3K27M being more oncogenic in Nestin+ cells than Olig2+ cells.

Original language	English (US)
Pages (from-to)	1681-1698
Number of pages	18
Journal	Glia
Volume	70
Issue number	9
DOIs	https://doi.org/10.1002/glia.24189
State	Published - Sep 2022

Funding

This work was supported by NIH grants K02 NS086917, R01 CA197313, R21 1R21NS114431\u201001, Rory David Deutsch Foundation, Madox's Warriors, DIPG Collaborative, the Cure Starts Now Foundation, the ChadTough Foundation, Cure Starts Now Australia, The Julian Boivin Courage for Cures Foundation, Hope for Caroline Foundation, Lauren's Fight for Cure Foundation, Aidan's Avengers Foundation, Austin Strong Foundation, Brooke Healey Foundation, Cure Brain Cancer Foundation, Grant's Ginormous Gift Foundation, Michael Mosier Defeat DIPG Foundation, Musella Foundation, Operation Grace White Foundation, Smiles for Sophie Foundation, Jeffrey Thomas Hayden Foundation, Pray Hope Believe Foundation, Ellie DIPG Research Fund, Julia Barbara Foundation, Ryan's Hope Foundation, Benny's World Foundation, Canadian Children's Brain Cancer Foundation, Reflections Of Grace Foundation, American Childhood Cancer Organization, Danni Kemp Cancer Research Fund, Love, Chloe Foundation, Smile for Brooklyn Foundation, The Kira Foundation, and the Wayland Villars DIPG Foundation. This work was supported by NIH grants K02 NS086917, R01 CA197313, R21 1R21NS114431-01, Rory David Deutsch Foundation, Madox's Warriors, DIPG Collaborative, the Cure Starts Now Foundation, the ChadTough Foundation, Cure Starts Now Australia, The Julian Boivin Courage for Cures Foundation, Hope for Caroline Foundation, Lauren's Fight for Cure Foundation, Aidan's Avengers Foundation, Austin Strong Foundation, Brooke Healey Foundation, Cure Brain Cancer Foundation, Grant's Ginormous Gift Foundation, Michael Mosier Defeat DIPG Foundation, Musella Foundation, Operation Grace White Foundation, Smiles for Sophie Foundation, Jeffrey Thomas Hayden Foundation, Pray Hope Believe Foundation, Ellie DIPG Research Fund, Julia Barbara Foundation, Ryan's Hope Foundation, Benny's World Foundation, Canadian Children's Brain Cancer Foundation, Reflections Of Grace Foundation, American Childhood Cancer Organization, Danni Kemp Cancer Research Fund, Love, Chloe Foundation, Smile for Brooklyn Foundation, The Kira Foundation, and the Wayland Villars DIPG Foundation.

Keywords

H3K27M
diffuse intrinsic pontine glioma
diffuse midline glioma
oligodendrocyte progenitor cells

ASJC Scopus subject areas

Neurology
Cellular and Molecular Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/glia.24189

Cite this

Tomita, Y., Shimazu, Y., Somasundaram, A., Tanaka, Y., Takata, N., Ishi, Y., Gadd, S., Hashizume, R., Angione, A., Pinero, G., Hambardzumyan, D., Brat, D. J., Hoeman, C. M., & Becher, O. J. (2022). A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M. Glia, 70(9), 1681-1698. https://doi.org/10.1002/glia.24189

@article{a6f1c32b957a4a99be36e782fdaeba69,

title = "A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M",

abstract = "Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A or PDGF-B overexpression, along with p53 deletion, resulted in gliomas in both models. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, both in PDGF-A and PDGF-B-driven models, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. RNA-sequencing analysis revealed that the differentially expressed genes in H3.3K27M tumors were non-overlapping between Olig2;PDGF-B, Olig2;PDGF-A, and Nestin;PDGF-A models. GSEA analysis of PDGFA tumors confirmed that the transcriptomal effects of H3.3K27M are cell-of-origin dependent with H3.3K27M promoting epithelial-to-mesenchymal transition (EMT) and angiogenesis when Olig2 marks the cell-of-origin and inhibiting EMT and angiogenesis when Nestin marks the cell-of-origin. We did observe some overlap with H3.3K27M promoting negative enrichment of TNFA_Signaling_Via_NFKB in both models. Our study suggests that the tumorigenic effects of H3.3K27M are cell-of-origin dependent, with H3.3K27M being more oncogenic in Nestin+ cells than Olig2+ cells.",

keywords = "H3K27M, diffuse intrinsic pontine glioma, diffuse midline glioma, oligodendrocyte progenitor cells",

author = "Yusuke Tomita and Yosuke Shimazu and Agila Somasundaram and Yoshihiro Tanaka and Nozomu Takata and Yukitomo Ishi and Samantha Gadd and Rintaro Hashizume and Angelo Angione and Gonzalo Pinero and Dolores Hambardzumyan and Brat, {Daniel J.} and Hoeman, {Christine M.} and Becher, {Oren J.}",

note = "Funding Information: This work was supported by NIH grants K02 NS086917, R01 CA197313, R21 1R21NS114431‐01, Rory David Deutsch Foundation, Madox's Warriors, DIPG Collaborative, the Cure Starts Now Foundation, the ChadTough Foundation, Cure Starts Now Australia, The Julian Boivin Courage for Cures Foundation, Hope for Caroline Foundation, Lauren's Fight for Cure Foundation, Aidan's Avengers Foundation, Austin Strong Foundation, Brooke Healey Foundation, Cure Brain Cancer Foundation, Grant's Ginormous Gift Foundation, Michael Mosier Defeat DIPG Foundation, Musella Foundation, Operation Grace White Foundation, Smiles for Sophie Foundation, Jeffrey Thomas Hayden Foundation, Pray Hope Believe Foundation, Ellie DIPG Research Fund, Julia Barbara Foundation, Ryan's Hope Foundation, Benny's World Foundation, Canadian Children's Brain Cancer Foundation, Reflections Of Grace Foundation, American Childhood Cancer Organization, Danni Kemp Cancer Research Fund, Love, Chloe Foundation, Smile for Brooklyn Foundation, The Kira Foundation, and the Wayland Villars DIPG Foundation. Publisher Copyright: {\textcopyright} 2022 The Authors. GLIA published by Wiley Periodicals LLC.",

year = "2022",

month = sep,

doi = "10.1002/glia.24189",

language = "English (US)",

volume = "70",

pages = "1681--1698",

journal = "Glia",

issn = "0894-1491",

publisher = "John Wiley & Sons Inc.",

number = "9",

}

Tomita, Y, Shimazu, Y, Somasundaram, A, Tanaka, Y, Takata, N, Ishi, Y, Gadd, S, Hashizume, R, Angione, A, Pinero, G, Hambardzumyan, D, Brat, DJ, Hoeman, CM & Becher, OJ 2022, 'A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M', Glia, vol. 70, no. 9, pp. 1681-1698. https://doi.org/10.1002/glia.24189

TY - JOUR

T1 - A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M

AU - Tomita, Yusuke

AU - Shimazu, Yosuke

AU - Somasundaram, Agila

AU - Tanaka, Yoshihiro

AU - Takata, Nozomu

AU - Ishi, Yukitomo

AU - Gadd, Samantha

AU - Hashizume, Rintaro

AU - Angione, Angelo

AU - Pinero, Gonzalo

AU - Hambardzumyan, Dolores

AU - Brat, Daniel J.

AU - Hoeman, Christine M.

AU - Becher, Oren J.

N1 - Funding Information: This work was supported by NIH grants K02 NS086917, R01 CA197313, R21 1R21NS114431‐01, Rory David Deutsch Foundation, Madox's Warriors, DIPG Collaborative, the Cure Starts Now Foundation, the ChadTough Foundation, Cure Starts Now Australia, The Julian Boivin Courage for Cures Foundation, Hope for Caroline Foundation, Lauren's Fight for Cure Foundation, Aidan's Avengers Foundation, Austin Strong Foundation, Brooke Healey Foundation, Cure Brain Cancer Foundation, Grant's Ginormous Gift Foundation, Michael Mosier Defeat DIPG Foundation, Musella Foundation, Operation Grace White Foundation, Smiles for Sophie Foundation, Jeffrey Thomas Hayden Foundation, Pray Hope Believe Foundation, Ellie DIPG Research Fund, Julia Barbara Foundation, Ryan's Hope Foundation, Benny's World Foundation, Canadian Children's Brain Cancer Foundation, Reflections Of Grace Foundation, American Childhood Cancer Organization, Danni Kemp Cancer Research Fund, Love, Chloe Foundation, Smile for Brooklyn Foundation, The Kira Foundation, and the Wayland Villars DIPG Foundation. Publisher Copyright: © 2022 The Authors. GLIA published by Wiley Periodicals LLC.

PY - 2022/9

Y1 - 2022/9

N2 - Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A or PDGF-B overexpression, along with p53 deletion, resulted in gliomas in both models. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, both in PDGF-A and PDGF-B-driven models, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. RNA-sequencing analysis revealed that the differentially expressed genes in H3.3K27M tumors were non-overlapping between Olig2;PDGF-B, Olig2;PDGF-A, and Nestin;PDGF-A models. GSEA analysis of PDGFA tumors confirmed that the transcriptomal effects of H3.3K27M are cell-of-origin dependent with H3.3K27M promoting epithelial-to-mesenchymal transition (EMT) and angiogenesis when Olig2 marks the cell-of-origin and inhibiting EMT and angiogenesis when Nestin marks the cell-of-origin. We did observe some overlap with H3.3K27M promoting negative enrichment of TNFA_Signaling_Via_NFKB in both models. Our study suggests that the tumorigenic effects of H3.3K27M are cell-of-origin dependent, with H3.3K27M being more oncogenic in Nestin+ cells than Olig2+ cells.

AB - Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A or PDGF-B overexpression, along with p53 deletion, resulted in gliomas in both models. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, both in PDGF-A and PDGF-B-driven models, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. RNA-sequencing analysis revealed that the differentially expressed genes in H3.3K27M tumors were non-overlapping between Olig2;PDGF-B, Olig2;PDGF-A, and Nestin;PDGF-A models. GSEA analysis of PDGFA tumors confirmed that the transcriptomal effects of H3.3K27M are cell-of-origin dependent with H3.3K27M promoting epithelial-to-mesenchymal transition (EMT) and angiogenesis when Olig2 marks the cell-of-origin and inhibiting EMT and angiogenesis when Nestin marks the cell-of-origin. We did observe some overlap with H3.3K27M promoting negative enrichment of TNFA_Signaling_Via_NFKB in both models. Our study suggests that the tumorigenic effects of H3.3K27M are cell-of-origin dependent, with H3.3K27M being more oncogenic in Nestin+ cells than Olig2+ cells.

KW - H3K27M

KW - diffuse intrinsic pontine glioma

KW - diffuse midline glioma

KW - oligodendrocyte progenitor cells

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A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M

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