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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 38 Issue 2 Pg. 110216 (01 11 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 35021084 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

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

Topics

• Animals
• Brain Neoplasms (metabolism)
• Cell Cycle (genetics)
• Cell Cycle Checkpoints (genetics)
• Cell Line, Tumor
• Checkpoint Kinase 1 (metabolism, 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, metabolism)