Histone Mutation and Tumor Development in Diffused Intrinsic Pontine Gliomas

Diffuse intrinsic pontine glioma (DIPG) is an aggressive primary brain tumor found exclusively in children. The median survival for children with DIPGs is about one year from diagnosis, and no cure is available. Well over 100 clinical trials have been performed to evaluate various chemotherapeutic regimens in these tumors without success.

Recently, somatic mutations in the histone H3 genes have been identified in the majority of high-grade pediatric glioma cases including DIPG; the predominant mutation leads to an amino acid change at lysine (K) 27 residue of H3.3 to methionine (M). In the right cellular context and developmental time frame, this mutation has been shown to be a driver of tumor genesis. The phenotypic hallmark for H3K27M tumors is global reduction of H3K27 trimethylation, which reprograms the epigenetic landscape and likely leads to unique therapeutic vulnerabilities in these tumors. These unique therapeutic vulnerabilities can then be used to treat these deadly tumors.

The long-term goal of Dr. Daniels' research team in the Experimental Drug and Therapeutics for Pediatric Brain Tumor Lab at Mayo Clinic is to develop new drugs and treatment paradigms for children with DIPG tumors by understanding how the H3K27M histone mutation contributes to therapeutic vulnerabilities in DIPG tumor cells.