Investigating the Role of Oncogenic H3.3 p.K27M Mutation in Diffuse Intrinsic Pontine Glioma
Year: 2024
Type: dissertation
Abstract: Diffuse Intrinsic Pontine Glioma (DIPG) is a pediatric high-grade glioma that diffusely penetrates the brainstem and is the leading cause of pediatric brain-tumour related death. With a median survival rate of less than 1 year, there is a desperate need to improve this prognosis. Factors contributing to this poor survival include its location in the brainstem which precludes surgical resection. In addition, a lack of pre-clinical in vivo models elucidating tumour formation and with which to test novel therapeutic approaches has hampered progress towards improved prognoses. A breakthrough in our knowledge of DIPG biology was the discovery of recurrent mutations in histone H3 genes in ~80% of DIPGs. The mutation results in a lysine to methionine substitution at amino acid 27 (K27M), leading to the reorganization of the H3K27me3 repressive mark. Despite these important findings we still do not know how H3.3 p.K27M promotes DIPG tumourigenesis. To investigate this, our lab has designed a novel transgenic model expressing H3.3 p.K27M mutation under control of a tet-repressible, cre-recombinase system, enabling both spatial and temporal analysis of its oncogenic properties. Given their co-occurrence in DIPG, I bred H3.3 p.K27M mice to others harbouring cre-inducible Trp53-deletions and/or constitutively active PDGFRαV461D. Driven in specific cellular populations by Nestin-, GFAP-, or Olig2-cre, mice developed diffusely infiltrative, brainstem-penetrant tumours bearing DIPG histological features. Differences in tumour latency, anatomical development, infiltration, and overall survival were found across all three mouse lines depending on the cell-of-origin. Notably, Nestin-cre tumours possessing H3.3 p.K27M show diffuse infiltration of the pons, while those lacking H3.3 p.K27M show little brainstem penetrance, suggesting H3.3 p.K27M as a driver of brainstem localization. The creation of this model is complemented by the investigation into two novel therapeutic approaches for DIPG involving the inhibition of epigenetic players and leveraging a ‘comorbidity’ of increased oxidative stress and dysregulated metabolism specific to H3.3 p.K27M-mutant cells. Collectively, these experiments provide novel insight into the role of H3.3 p.K27M in defining tumour location, describe a novel model for the development of DIPG therapies, and describe a new approach for DIPG treatment.
Source: TSpace (University of Toronto)
Author: Lubanszky, Evan
Institution: University of Toronto
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7133096383