Pediatric high-grade astrocytoma (pHGA), which diffusely infiltrates the brain, is the main cause of brain tumor death in children, with near 100% fatality. A lack of targeted therapies and pediatric-specific pre-clinical models contribute to this poor survival. Sequencing efforts, by us and others have led to the seminal discovery of histone H3 mutations in pHGA, highlighting the importance of epigenetic alterations in this disease. Understanding the biological consequences of this mutation is required to develop effective therapies to target these tumors.
What are the goals of this project?
We aim to elucidate the biological consequences of the H3.3G34R histone mutation, how it drives tumorigenesis, and how it can be targeted therapeutically.
What is the impact of this project?
High grade astrocytoma is the main cause of pediatric brain tumor death. Decades of clinical trials, largely informed by work on adult brain tumors, have been ineffective at improving their treatment. The discovery of frequent H3G34R mutations in these tumors suggests that histone biology plays a critical role in their development. However, the nature of that role remains unknown. These studies will be important for understanding the biological tumorigenic function of H3G34R mutations and how they can be targeted therapeutically.
Why the CBTN request is important to this project?
The patient derived cell lines will be used to validate the findings from our BioID screen. They will be essential in that they represent an endogenously expressing H3.3G34R mutant line. Further, they will be critical for determining the clinical significance of our findings and for testing potential novel therapeutic approaches.
The Children's Brain Tumor Network contributed to this project by providing cell lines and access to the Pediatric Brain Tumor Atlas.
Byungjin Kim, Graduate Student
Laura Canty, Research Technician
High-grade glioma/astrocytoma (WHO grade III/IV)
High-grade Gliomas (HGG) in children nearly always result in a dismal prognosis. Although novel therapeutic approaches are currently in development, preclinical testing has been limited, due to a lack of pediatric specific HGG preclinical models. These models are needed to help test the effective