Det kliniska värdet av MYC-drivna epitranskriptionella nätverk i Burkitts lymfom hos barn

Burkitt Lymphoma (BL) is a type of blood cancer prevalent in children. BL diagnoses are more frequent in children than adults, indicating there may be a specific pediatric BL that differs from adult cases. In this proposal, we aim to better understand the molecular pathways that underlie pediatric BL. The Bellodi lab studies how RNA modifications regulate cellular processes, including cancer. RNA modifications help regulate the RNA and protein content of a cell by affecting RNA stability, RNA structure, and protein synthesis. Pseudouridylation (Ψ) is the most common RNA modification and is catalyzed by enzymes such as PUS7. PUS7 regulates protein synthesis in hematopoietic stem cells by modifying specific RNA molecules. Disruption of PUS7 can lead to leukemia and other cancers. However, how PUS7 promotes cancer development is poorly understood. Our preliminary results indicate that PUS7 is regulated by MYC, a potent oncogene representing the primary genetic alteration in BL. Hence, this project intends to characterize the effects of PUS7 and Ψ in pediatric BL. First, we will use a mouse model of BL in which we delete the PUS7 gene, enabling us to precisely evaluate how malignant B cells respond to these perturbations and how PUS7 loss impacts translation and Ψ. Second, we will identify genes regulated by PUS7 in this model. We will use human cell lines derived from pediatric BL patients to characterize the effects of PUS7 in human pediatric disease and validate the importance of the genes we identified in mice. We will implant these cells into mice to assess how PUS7 impacts the aggressiveness of pediatric BL. Third, we will verify the expression of PUS7 and our candidate genes in pediatric BL patient tissue samples. Collectively, our studies will provide a comprehensive characterization of the importance of PUS7-mediated Ψ in pediatric Burkitt Lymphoma and may uncover novel diagnostic and therapeutic targets in this disease driven by the undruggable oncogene MYC.