Identifying Disease Mechanisms and Therapeutic Opportunities in Pediatric Low-grade Gliomas Driven by MYB-QKI Fusions
Brain tumors are the most common pediatric solid tumors. Low-grade gliomas (LGGs) are the most common pediatric brain tumors. Most become quiescent in early adulthood yet are debilitating during childhood. They can cause elevated intracranial pressure, nausea, vision loss, hormonal deficiency, failure to thrive, seizures and/or behavior changes. Complete surgical resection is often impossible. Unresectable or recurrent tumors require chemotherapy. Severe side-effects include hearing loss, infertility, secondary malignancy and/or hematologic disorders. Resistant tumors require radiation, which can irreversibly impair cognition. Safe therapies are needed.
Our laboratories completed a genetic study of pediatric LGGs. We identified a chromosome abnormality as the cause of angiocentric glioma (AG), a subtype of pediatric LGG: two genes, MYB and QKI, are truncated and fused to each other. MYB normally promotes cellular growth and QKI suppresses it. MYB-QKI causes tumors for unknown reasons. Understanding how a disease-causing gene functions is critical to designing therapies that block it.
We will study how MYB-QKI functions to design new therapies. This proposal emphasizes QKI because it is poorly characterized. QKI genetic alterations are frequent in cancer. Since normal QKI binds to RNA molecules, we will identify the RNAs that bind to MYB-QKI and their roles in AG. Since QKI is controlled by other proteins, we will identify those that control MYB-QKI. Finally, we will search genome-wide for genes that cooperate with MYB-QKI. All findings represent potential therapeutic targets. We previously observed that MYB-QKI activates other genes, including CDK6 and KIT. CDK6 and KIT inhibitors will be tested against MYB-QKI.