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

Cell Rep. 2022 Jan 11;38(2):110216. doi: 10.1016/j.celrep.2021.110216.

Authors

Tingting Qin¹, Brendan Mullan², Ramya Ravindran², Dana Messinger², Ruby Siada², Jessica R Cummings², Micah Harris², Ashwath Muruganand², Kalyani Pyaram³, Zachary Miklja², Mary Reiber², Taylor Garcia², Dustin Tran², Carla Danussi⁴, Jacqueline Brosnan-Cashman⁵, Drew Pratt⁶, Xinyi Zhao⁷, Alnawaz Rehemtulla⁷, Maureen A Sartor⁸, Sriram Venneti⁶, Alan K Meeker⁵, Jason T Huse⁴, Meredith A Morgan⁷, Pedro R Lowenstein⁹, Maria G Castro⁹, Viveka Nand Yadav², Carl Koschmann¹⁰

Affiliations

¹ Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA.
³ Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
⁴ Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁶ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁷ Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁸ Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁹ Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
¹⁰ Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address: ckoschma@med.umich.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Neoplasms / metabolism
Cell Cycle / genetics
Cell Cycle Checkpoints / genetics
Cell Line, Tumor
Checkpoint Kinase 1 / metabolism*
Checkpoint Kinase 1 / physiology
Female
Glioma / metabolism*
Histones / metabolism
Humans
Isocitrate Dehydrogenase / genetics
Male
Mice
Mice, Inbred C57BL
Mutation
Neoplasm Recurrence, Local / metabolism
Primary Cell Culture
X-linked Nuclear Protein / genetics
X-linked Nuclear Protein / metabolism*

Substances

Histones
Isocitrate Dehydrogenase
CHEK1 protein, human
Checkpoint Kinase 1
Chek1 protein, mouse
ATRX protein, human
Atrx protein, mouse
X-linked Nuclear Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding