HG-78: SYNTHETIC LETHAL EPIGENETIC INTERACTIONS IN K27M MUTATED DIPG

DIPG (Diffuse Intrinsic Pontine Gliomas) is a brain stem tumor which affects children between the age of 6 and 9 years old. These tumors are very aggressive and inoperable due to their location, resulting in a 0% survival rate. While the importance of identifying new agents for DIPG therapeutics has long been appreciated, progress has been limited. Whole-genome sequencing has identified histone H3K27M mutations in DIPG tumors that result in deregulation of the epigenetic code. However, there is limited understanding of the functional roles epigenetic regulators play in controlling DIPG tumorigenesis. We hypothesized that other key epigenetic regulators provide DIPG cells with a survival advantage in the presence of a H3K27M mutation. To address this, we performed a shRNA-based functional genomic screen in H3K27M mutant DIPG cells by targeting 408 epigenetic genes. One of our top hits was BMI1, which is a part of the PRC1 complex. PRC1 regulates cell self-renewal and stem cell behavior in both normal and tumor cells. Stable knockdown of BMI1 in DIPG cells decreased cell proliferation, cell self-renewal capacity and decreased stem cell markers. BMI1 depletion enhances the effect of radiation in DIPG cells, as measured by cell colony formation. In addition, PTC-209, a small-molecule inhibitor of BMI, decreased the stem cell expression and growth in DIPG cells. These studies suggest that targeting BMI1 in DIPG tumors in patients before giving the standard-of-care bolus radiation could be a more effective treatment.