Identifying Epistatic Suppressors of Oncohistone in Pediatric High-Grade Gliomas
In the cell, DNA strands are bound to structural proteins called histones to form chromatin; this in turn, facilitates the packaging of the genetic material to fit into the nucleus. The expression of genetic material can be enhanced or repressed by modification of such histones. Previously, our lab identified a high prevalence of mutations in the histone H3 gene in lethal childhood brain cancer. One of the mutations replaces the 27th amino acid residue lysine with methionine (H3K27M) creating a mutant histone that drastically disrupts chromatin modifications, leading to abnormal gene expression and tumour formation along the midline of the brain. Such tumours are impossible to surgically remove, and conventional therapies universally fail; raising an urgent need to identify novel means of disease treatment. Some recent studies have shown that these cancer cells may be respond to drugs that disrupts chromatin modification, but since these are processes that maintain normal cells, they may be unsafe to use in patients.
Our long-term goal is to identify relevant and safe therapeutic targets for the treatment of these childhood brain cancers. We think that these chromatin perturbations and the disease may be reversible by genetic deletion of specific enzymes that modify the chromatin. Using a fruit fly model, depletion of one such chromatin modifier is indeed able to suppress tumors and defects associated with the H3K27M mutation but showed limited toxicity in normal flies. Using gene-editing on cell lines established from pediatric brain tumours containing H3K27M, we will assess whether depletion of this enzyme can abolish the tumorigenic activity of the mutation. The results from this study could potentially result in highly specific therapeutic targets for this deadly form of cancer.