Oral Presentation 46th Lorne Genome Conference 2025

RNA Polymerase I inhibition as a therapeutic strategy for treating H3.3 and ATRX mutated gliomas. (114911)

Andrew Garvie 1 , Lee Wong 1 , Linda Hii 1 , Maheshi Udugama 1 , Hsiao Voon 1 , Jeffrey Mann 1 , Ross Hannan 2 , Ron Firestein 3 , Jieqiong Lou 4 , Jill Danne 5 , Nada Jabado 6
  1. Monash University, Mitcham, VICTORIA, Australia
  2. Genome Sciences and Cancer Division, ANU, Acton, Canberra, Australia
  3. Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia
  4. Biochemistry and Molecular Biology, The Melbourne University, Melbourne, Victoria, Australia
  5. Cryo-EM Monash Department, Monash University, Clayton, Victoria, Australia
  6. Medicine, Mcgill, Montreal, Qubec, Canada

The deposition of histone H3.3 by the ATRX/DAXX chaperone complex is critical for heterochromatin formation and DNA stability, particularly within ribosomal DNA (rDNA) repeats. Our prior research demonstrated that ATRX-deficient cancer cells experience significant rDNA repeat loss, which disrupts ribosomal RNA (rRNA) transcription and increases susceptibility to RNA Polymerase I (Pol I) inhibition (Udugama et al., 2018). Here, we expand these findings to pediatric high-grade gliomas (pHGGs) with histone H3.3 mutations—specifically H3.3 K27M and G34R—highlighting similar disruptions in rRNA transcription machinery.

Our results show that H3.3 mutations lead to marked reductions in rRNA synthesis and alter upstream binding factor (UBF1/2) localization. This phenomenon was observed in both H3.3-mutant mouse embryonic stem cells and pHGG tumor samples. Notably, patient-derived pHGG cell lines with H3.3 mutations exhibited heightened sensitivity to RNA Pol I inhibitors, suggesting a potential therapeutic angle for targeting rRNA transcription in these gliomas.

Furthermore, we propose that H3.3/ATRX status, combined with distinct UBF1/2 staining patterns, could serve as predictive biomarkers for Pol I inhibitor responsiveness. These findings underscore the potential of exploiting rRNA transcriptional instability as a therapeutic strategy for H3.3/ATRX-mutated gliomas—a promising approach that may improve treatment outcomes for pHGG patients with these mutations.

 

 

  1. Udugama, M., Sanij, E., Voon, H. P. J., Son, J., Hii, L., Henson, J. D., Chan, F. L., Chang, F. T. M., Liu, Y., Pearson, R. B., Kalitsis, P., Mann, J. R., Collas, P., Hannan, R. D., and Wong, L. H. (2018) Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers, Proc Natl Acad Sci U S A 115, 4737-4742.