EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas

Faizaan Mohammad; Simon Weissmann; Benjamin Olivier Leblanc; Deo Prakash Pandey; Jonas Westergaard Højfeldt; Itys Comet; Chunqin Zheng; Jens Vilstrup Johansen; Nicolas Philippe Jean-Pierre Rapin; Bo Torben Porse; Andrey Tvardovskiy; Ole N Jensen; Nagore G. Olaciregui; Cinzia Lavarino; Mariona Suñol; Carmen de Torres; Jaume Mora; Angel M. Carcaboso; Kristian Helin

doi:10.1038/nm.4293

EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas

Faizaan Mohammad, Simon Weissmann, Benjamin Olivier Leblanc, Deo Prakash Pandey, Jonas Westergaard Højfeldt, Itys Comet, Chunqin Zheng, Jens Vilstrup Johansen, Nicolas Philippe Jean-Pierre Rapin, Bo Torben Porse, Andrey Tvardovskiy, Ole N Jensen, Nagore G. Olaciregui, Cinzia Lavarino, Mariona Suñol, Carmen de Torres, Jaume Mora, Angel M. Carcaboso, Kristian Helin

206 Citationer (Scopus)

Abstract

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for the methylation of H3 at lysine 27 (H3K27me), by binding to its catalytic subunit EZH2. Although DIPGs with the H3K27M mutation show global loss of H3K27me3, several genes retain H3K27me3. Here we describe a mouse model of DIPG in which H3K27M potentiates tumorigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M-expressing tumors require PRC2 for proliferation. Furthermore, we demonstrate that small-molecule EZH2 inhibitors abolish tumor cell growth through a mechanism that is dependent on the induction of the tumor-suppressor protein p16(INK4A). Genome-wide enrichment analyses show that the genes that retain H3K27me3 in H3K27M cells are strong polycomb targets. Furthermore, we find a highly significant overlap between genes that retain H3K27me3 in the DIPG mouse model and in human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M-expressing DIPGs, and that inhibition of EZH2 is a potential therapeutic strategy for the treatment of these tumors.

Originalsprog	Engelsk
Tidsskrift	Nature Medicine
Vol/bind	23
Udgave nummer	4
Sider (fra-til)	483-492
Antal sider	10
ISSN	1078-8956
DOI	https://doi.org/10.1038/nm.4293
Status	Udgivet - 1 apr. 2017

Adgang til dokumentet

10.1038/nm.4293

Citationsformater

Mohammad, F., Weissmann, S., Leblanc, B. O., Pandey, D. P., Højfeldt, J. W., Comet, I., Zheng, C., Johansen, J. V., Rapin, N. P. J-P., Porse, B. T., Tvardovskiy, A., Jensen, O. N., Olaciregui, N. G., Lavarino, C., Suñol, M., de Torres, C., Mora, J., Carcaboso, A. M., & Helin, K. (2017). EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nature Medicine, 23(4), 483-492. https://doi.org/10.1038/nm.4293

Mohammad, F, Weissmann, S, Leblanc, BO, Pandey, DP, Højfeldt, JW, Comet, I, Zheng, C, Johansen, JV, Rapin, NPJ-P, Porse, BT, Tvardovskiy, A, Jensen, ON, Olaciregui, NG, Lavarino, C, Suñol, M, de Torres, C, Mora, J, Carcaboso, AM & Helin, K 2017, 'EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas', Nature Medicine, bind 23, nr. 4, s. 483-492. https://doi.org/10.1038/nm.4293

@article{af0c3a34b3b049358f3022d42c058fa4,

title = "EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas",

abstract = "Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for the methylation of H3 at lysine 27 (H3K27me), by binding to its catalytic subunit EZH2. Although DIPGs with the H3K27M mutation show global loss of H3K27me3, several genes retain H3K27me3. Here we describe a mouse model of DIPG in which H3K27M potentiates tumorigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M-expressing tumors require PRC2 for proliferation. Furthermore, we demonstrate that small-molecule EZH2 inhibitors abolish tumor cell growth through a mechanism that is dependent on the induction of the tumor-suppressor protein p16(INK4A). Genome-wide enrichment analyses show that the genes that retain H3K27me3 in H3K27M cells are strong polycomb targets. Furthermore, we find a highly significant overlap between genes that retain H3K27me3 in the DIPG mouse model and in human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M-expressing DIPGs, and that inhibition of EZH2 is a potential therapeutic strategy for the treatment of these tumors.",

keywords = "Journal Article",

author = "Faizaan Mohammad and Simon Weissmann and Leblanc, {Benjamin Olivier} and Pandey, {Deo Prakash} and H{\o}jfeldt, {Jonas Westergaard} and Itys Comet and Chunqin Zheng and Johansen, {Jens Vilstrup} and Rapin, {Nicolas Philippe Jean-Pierre} and Porse, {Bo Torben} and Andrey Tvardovskiy and Jensen, {Ole N} and Olaciregui, {Nagore G.} and Cinzia Lavarino and Mariona Su{\~n}ol and {de Torres}, Carmen and Jaume Mora and Carcaboso, {Angel M.} and Kristian Helin",

year = "2017",

month = apr,

day = "1",

doi = "10.1038/nm.4293",

language = "English",

volume = "23",

pages = "483--492",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "nature publishing group",

number = "4",

}

TY - JOUR

T1 - EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas

AU - Mohammad, Faizaan

AU - Weissmann, Simon

AU - Leblanc, Benjamin Olivier

AU - Pandey, Deo Prakash

AU - Højfeldt, Jonas Westergaard

AU - Comet, Itys

AU - Zheng, Chunqin

AU - Johansen, Jens Vilstrup

AU - Rapin, Nicolas Philippe Jean-Pierre

AU - Porse, Bo Torben

AU - Tvardovskiy, Andrey

AU - Jensen, Ole N

AU - Olaciregui, Nagore G.

AU - Lavarino, Cinzia

AU - Suñol, Mariona

AU - de Torres, Carmen

AU - Mora, Jaume

AU - Carcaboso, Angel M.

AU - Helin, Kristian

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for the methylation of H3 at lysine 27 (H3K27me), by binding to its catalytic subunit EZH2. Although DIPGs with the H3K27M mutation show global loss of H3K27me3, several genes retain H3K27me3. Here we describe a mouse model of DIPG in which H3K27M potentiates tumorigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M-expressing tumors require PRC2 for proliferation. Furthermore, we demonstrate that small-molecule EZH2 inhibitors abolish tumor cell growth through a mechanism that is dependent on the induction of the tumor-suppressor protein p16(INK4A). Genome-wide enrichment analyses show that the genes that retain H3K27me3 in H3K27M cells are strong polycomb targets. Furthermore, we find a highly significant overlap between genes that retain H3K27me3 in the DIPG mouse model and in human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M-expressing DIPGs, and that inhibition of EZH2 is a potential therapeutic strategy for the treatment of these tumors.

AB - Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for the methylation of H3 at lysine 27 (H3K27me), by binding to its catalytic subunit EZH2. Although DIPGs with the H3K27M mutation show global loss of H3K27me3, several genes retain H3K27me3. Here we describe a mouse model of DIPG in which H3K27M potentiates tumorigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M-expressing tumors require PRC2 for proliferation. Furthermore, we demonstrate that small-molecule EZH2 inhibitors abolish tumor cell growth through a mechanism that is dependent on the induction of the tumor-suppressor protein p16(INK4A). Genome-wide enrichment analyses show that the genes that retain H3K27me3 in H3K27M cells are strong polycomb targets. Furthermore, we find a highly significant overlap between genes that retain H3K27me3 in the DIPG mouse model and in human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M-expressing DIPGs, and that inhibition of EZH2 is a potential therapeutic strategy for the treatment of these tumors.

KW - Journal Article

U2 - 10.1038/nm.4293

DO - 10.1038/nm.4293

M3 - Journal article

C2 - 28263309

SN - 1078-8956

VL - 23

SP - 483

EP - 492

JO - Nature Medicine

JF - Nature Medicine

IS - 4

ER -

EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater