Deciphering Pathogenesis of Pediatric Gliomas

The long-term goal of this project is to elucidate the molecular pathogenesis underlying pediatric high-grad gliomas (HGGs). Glioblastoma is the most common and most aggressive malignant primary brain tumor in humans, which accounts for 52% of all functional tissue brain tumor cases. Despite decades of concerted therapeutic efforts, gliomas remain essentially incurable. The major problem is that the real pathogenesis underlying this disease is essentially unknown. Recent studies have identified defective histone H3 lysine 36 (H3K36) trimethyltransferase SETD2 and K27M and G34R/V substitution mutations in H3 variant H3.3 in ~80% of pediatric HGG. However, the mechanism(s) by which the abnormal SETD2 and H3.3 drive malignancy of pediatric HGGs is unknown. Interestingly, our recent studies showed that H3K36me3 is required for DNA mismatch repair (MMR), an important genome-maintenance system, by recruiting mismatch recognition protein hMutS? to chromatin through its direct interaction with hMutS?, and that cells depleted of H3K36me3/SETD2 display an MMR-deficient phenotype, including frequent alterations in simple repetitive DNA sequence, a phenomenon called microsatellite instability (MSI). Given that SETD2 is the only methyltransferase identified so far that is responsible for H3K36 trimethylation and that G34R/V and K27M substitutions in H3.3 directly or indirectly influence H3K36 trimethylation, we hypothesize that abnormal SETD2 and H3.3 promote pediatric HGGs by inactivating the MMR function through blocking H3K36 trimethylation. To test this hypothesis, two specific aims are proposed. Specific Aim 1 is to directly determine MMR-deficient phenotype in pediatric HGGs with SETD2 or H3.3 mutations. Specific Aim 2 is to determine in vivo MMR function in glioma cell lines defective in SETD2 and H3.3(G34R/V). A successful completion of the proposed study will reveal the real pathogenesis of pediatric HGGs, providing a novel biomarker for cancer detection. More importantly, given that tumor cells defective in MMR are highly resistant to many DNA damaging reagents including temozolomide that is widely used for and causes resistance in glioma therapy, this study will also provide new strategies to improve glioma therapy.