ATRX loss in glioma results in dysregulation of cell-cycle phase transition and ATM inhibitor radio-sensitization

Tingting Qin; Brendan Mullan; Ramya Ravindran; Dana Messinger; Ruby Siada; Jessica R. Cummings; Micah Harris; Ashwath Muruganand; Kalyani Pyaram; Zachary Miklja; Mary Reiber; Taylor Garcia; Dustin Tran; Carla Danussi; Jacqueline Brosnan-Cashman; Drew Pratt; Xinyi Zhao; Alnawaz Rehemtulla; Maureen A. Sartor; Sriram Venneti; Alan K. Meeker; Jason T. Huse; Meredith A. Morgan; Pedro R. Lowenstein; Maria G. Castro; Viveka Nand Yadav; Carl Koschmann

doi:10.1016/j.celrep.2021.110216

ATRX loss in glioma results in dysregulation of cell-cycle phase transition and ATM inhibitor radio-sensitization

Tingting Qin, Brendan Mullan, Ramya Ravindran, Dana Messinger, Ruby Siada, Jessica R. Cummings, Micah Harris, Ashwath Muruganand, Kalyani Pyaram, Zachary Miklja, Mary Reiber, Taylor Garcia, Dustin Tran, Carla Danussi, Jacqueline Brosnan-Cashman, Drew Pratt, Xinyi Zhao, Alnawaz Rehemtulla, Maureen A. Sartor, Sriram VennetiAlan K. Meeker, Jason T. Huse, Meredith A. Morgan, Pedro R. Lowenstein, Maria G. Castro, Viveka Nand Yadav, Carl Koschmann

Pathology

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

27 Scopus citations

Abstract

ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and isocitrate dehydrogenase (IDH)-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We find that ATRX binds the regulatory elements of cell-cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to the early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell-cycle regulator ATM with irradiation. Addition of the ATM inhibitor AZD0156 doubles median survival in mice intracranially implanted with ATRX-deficient GBM cells, which is not seen in ATRX-wild-type controls. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display Chk1-mediated dysregulation of cell-cycle phase transitions, which opens a window for therapies targeting this phenotype.

Original language	English (US)
Article number	110216
Journal	Cell Reports
Volume	38
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2021.110216
State	Published - Jan 11 2022

Keywords

ATM inhibitor
ATRX
CHEK1
cell-cycle
epigenetics
glioma

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2021.110216

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Qin, T., Mullan, B., Ravindran, R., Messinger, D., Siada, R., Cummings, J. R., Harris, M., Muruganand, A., Pyaram, K., Miklja, Z., Reiber, M., Garcia, T., Tran, D., Danussi, C., Brosnan-Cashman, J., Pratt, D., Zhao, X., Rehemtulla, A., Sartor, M. A., ... Koschmann, C. (2022). ATRX loss in glioma results in dysregulation of cell-cycle phase transition and ATM inhibitor radio-sensitization. Cell Reports, 38(2), Article 110216. https://doi.org/10.1016/j.celrep.2021.110216

Qin, T, Mullan, B, Ravindran, R, Messinger, D, Siada, R, Cummings, JR, Harris, M, Muruganand, A, Pyaram, K, Miklja, Z, Reiber, M, Garcia, T, Tran, D, Danussi, C, Brosnan-Cashman, J, Pratt, D, Zhao, X, Rehemtulla, A, Sartor, MA, Venneti, S, Meeker, AK, Huse, JT, Morgan, MA, Lowenstein, PR, Castro, MG, Yadav, VN & Koschmann, C 2022, 'ATRX loss in glioma results in dysregulation of cell-cycle phase transition and ATM inhibitor radio-sensitization', Cell Reports, vol. 38, no. 2, 110216. https://doi.org/10.1016/j.celrep.2021.110216

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title = "ATRX loss in glioma results in dysregulation of cell-cycle phase transition and ATM inhibitor radio-sensitization",

abstract = "ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and isocitrate dehydrogenase (IDH)-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We find that ATRX binds the regulatory elements of cell-cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to the early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell-cycle regulator ATM with irradiation. Addition of the ATM inhibitor AZD0156 doubles median survival in mice intracranially implanted with ATRX-deficient GBM cells, which is not seen in ATRX-wild-type controls. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display Chk1-mediated dysregulation of cell-cycle phase transitions, which opens a window for therapies targeting this phenotype.",

keywords = "ATM inhibitor, ATRX, CHEK1, cell-cycle, epigenetics, glioma",

author = "Tingting Qin and Brendan Mullan and Ramya Ravindran and Dana Messinger and Ruby Siada and Cummings, {Jessica R.} and Micah Harris and Ashwath Muruganand and Kalyani Pyaram and Zachary Miklja and Mary Reiber and Taylor Garcia and Dustin Tran and Carla Danussi and Jacqueline Brosnan-Cashman and Drew Pratt and Xinyi Zhao and Alnawaz Rehemtulla and Sartor, {Maureen A.} and Sriram Venneti and Meeker, {Alan K.} and Huse, {Jason T.} and Morgan, {Meredith A.} and Lowenstein, {Pedro R.} and Castro, {Maria G.} and Yadav, {Viveka Nand} and Carl Koschmann",

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year = "2022",

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doi = "10.1016/j.celrep.2021.110216",

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AU - Qin, Tingting

AU - Mullan, Brendan

AU - Ravindran, Ramya

AU - Messinger, Dana

AU - Siada, Ruby

AU - Cummings, Jessica R.

AU - Harris, Micah

AU - Muruganand, Ashwath

AU - Pyaram, Kalyani

AU - Miklja, Zachary

AU - Reiber, Mary

AU - Garcia, Taylor

AU - Tran, Dustin

AU - Danussi, Carla

AU - Brosnan-Cashman, Jacqueline

AU - Pratt, Drew

AU - Zhao, Xinyi

AU - Rehemtulla, Alnawaz

AU - Sartor, Maureen A.

AU - Venneti, Sriram

AU - Meeker, Alan K.

AU - Huse, Jason T.

AU - Morgan, Meredith A.

AU - Lowenstein, Pedro R.

AU - Castro, Maria G.

AU - Yadav, Viveka Nand

AU - Koschmann, Carl

PY - 2022/1/11

Y1 - 2022/1/11

N2 - ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and isocitrate dehydrogenase (IDH)-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We find that ATRX binds the regulatory elements of cell-cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to the early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell-cycle regulator ATM with irradiation. Addition of the ATM inhibitor AZD0156 doubles median survival in mice intracranially implanted with ATRX-deficient GBM cells, which is not seen in ATRX-wild-type controls. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display Chk1-mediated dysregulation of cell-cycle phase transitions, which opens a window for therapies targeting this phenotype.

AB - ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and isocitrate dehydrogenase (IDH)-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We find that ATRX binds the regulatory elements of cell-cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to the early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell-cycle regulator ATM with irradiation. Addition of the ATM inhibitor AZD0156 doubles median survival in mice intracranially implanted with ATRX-deficient GBM cells, which is not seen in ATRX-wild-type controls. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display Chk1-mediated dysregulation of cell-cycle phase transitions, which opens a window for therapies targeting this phenotype.

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KW - cell-cycle

KW - epigenetics

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VL - 38

JO - Cell Reports

JF - Cell Reports

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ER -

ATRX loss in glioma results in dysregulation of cell-cycle phase transition and ATM inhibitor radio-sensitization

Abstract

Keywords

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