Novel genetically engineered H3.3G34R model reveals cooperation with ATRX loss in upregulation of Hoxa cluster genes and promotion of neuronal lineage

Aalaa S. Abdallah, Herminio J. Cardona, Samantha L. Gadd, Daniel J. Brat, Plamena P. Powla, Waleed S. Alruwalli, Chen Shen, David J. Picketts, Xiao Nan Li, Oren J. Becher

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background. Pediatric high-grade gliomas (pHGGs) are aggressive pediatric CNS tumors and an important subset are characterized by mutations in H3F3A, the gene that encodes Histone H3.3 (H3.3). Substitution of Glycine at position 34 of H3.3 with either Arginine or Valine (H3.3G34R/V), was recently described and characterized in a large cohort of pHGG samples as occurring in 5-20% of pHGGs. Attempts to study the mechanism of H3.3G34R have proven difficult due to the lack of knowledge regarding the cell-of-origin and the requirement for co-occurring mutations for model development. We sought to develop a biologically relevant animal model of pHGG to probe the downstream effects of the H3.3G34R mutation in the context of vital co-occurring mutations. Methods. We developed a genetically engineered mouse model (GEMM) that incorporates PDGF-A activation, TP53 loss and the H3.3G34R mutation both in the presence and loss of Alpha thalassemia/mental retardation syndrome X-linked (ATRX), which is commonly mutated in H3.3G34 mutant pHGGs. Results. We demonstrated that ATRX loss significantly increases tumor latency in the absence of H3.3G34R and inhibits ependymal differentiation in the presence of H3.3G34R.Transcriptomic analysis revealed that ATRX loss in the context of H3.3G34R upregulates Hoxa cluster genes. We also found that the H3.3G34R overexpression leads to enrichment of neuronal markers but only in the context of ATRX loss. Conclusions. This study proposes a mechanism in which ATRX loss is the major contributor to many key transcriptomic changes in H3.3G34R pHGGs.

Original languageEnglish
Article numbervdad003
JournalNeuro-Oncology Advances
Volume5
Issue number1
DOIs
StatePublished - 1 Jan 2023
Externally publishedYes

Keywords

  • ATRX
  • GEMM
  • H3.3G34R
  • HOXA
  • RCAS
  • mouse models
  • pediatric high-grade glioma

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