Simultaneous Nbs1 and p53 inactivation in neural progenitors triggers high-grade gliomas

David E. Reuss, Susanna M. Downing, Cristel V. Camacho, Yong Dong Wang, Rosario M. Piro, Christel Herold-Mende, Zhao Qi Wang, Thomas G. Hofmann, Felix Sahm, Andreas von Deimling, Peter J. McKinnon, Pierre Olivier Frappart

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Aims: Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder caused by hypomorphic mutations of NBS1. NBS1 is a member of the MRE11-RAD50-NBS1 (MRN) complex that binds to DNA double-strand breaks and activates the DNA damage response (DDR). Nbs1 inactivation in neural progenitor cells leads to microcephaly and premature death. Interestingly, p53 homozygous deletion rescues the NBS1-deficient phenotype allowing long-term survival. The objective of this work was to determine whether simultaneous inactivation of Nbs1 and p53 in neural progenitors triggered brain tumorigenesis and if so in which category this tumour could be classified. Methods: We generated a mouse model with simultaneous genetic inactivation of Nbs1 and p53 in embryonic neural stem cells and analysed the arising tumours with in-depth molecular analyses including immunohistochemistry, array comparative genomic hybridisation (aCGH), whole exome-sequencing and RNA-sequencing. Results: NBS1/P53-deficient mice develop high-grade gliomas (HGG) arising in the olfactory bulbs and in the cortex along the rostral migratory stream. In-depth molecular analyses using immunohistochemistry, aCGH, whole exome-sequencing and RNA-sequencing revealed striking similarities to paediatric human HGG with shared features with radiation-induced gliomas (RIGs). Conclusions: Our findings show that concomitant inactivation of Nbs1 and p53 in mice promotes HGG with RIG features. This model could be useful for preclinical studies to improve the prognosis of these deadly tumours, but it also highlights the singularity of NBS1 among the other DNA damage response proteins in the aetiology of brain tumours.

Original languageEnglish (US)
Article numbere12915
JournalNeuropathology and Applied Neurobiology
Volume49
Issue number4
DOIs
StatePublished - Aug 2023
Externally publishedYes

Keywords

  • NBS1
  • P53
  • PDGFRA
  • genomic rearrangements
  • high-grade glioma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Neurology
  • Clinical Neurology
  • Physiology (medical)

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