Doctor of Philosophy, The Ohio State University, 2021, Biomedical Sciences

Ewing sarcoma is an aggressive bone and soft tissue-associated cancer affecting pediatric, adolescent, and young adult patients. Despite general improvement in pediatric cancer outcomes due to novel therapeutic options, Ewing sarcoma treatment, which consists of high-dose chemotherapy, radiation, and/or local surgical control, has remained largely unchanged for several decades and patients with metastatic disease continue to see poor outcomes. Although pediatric cancers often have far fewer mutational events than adult cancers, Ewing sarcoma is particularly interesting as the disease is often characterized by a sole chromosomal translocation event: These chromosomal translocations fuse one of the FET protein family members, a group of putative RNA-binding proteins, to a member of the ETS transcription factor family. As these FET/ETS fusion proteins have been determined to function as oncogenic transcription factors responsible for driving Ewing sarcomagenesis, it is critical that the biological mechanisms these fusions utilize to facilitate this process are elucidated. Despite discovery of several FET/ETS translocations, the majority of studies in the field focus on EWS/FLI, as it is the most common fusion observed in patients. Although these studies have provided a breadth of knowledge surrounding oncogenic function of the protein, there is a great deal of uncertainty how alternative FET/ETS fusions should be diagnosed and treated in the clinic. Herein, we characterize a novel FET/ETS fusion and perform the first comparative analysis on EWS/FLI and alternative, rarer FET/ETS fusion proteins. Our results reveal general similarities in DNA-binding and transcriptional regulation properties between the broad FET/ETS fusion group and provide the first tangible body of evidence to support that these fusions should indeed be classified as bona fide Ewing sarcoma tumors. Furthermore, we sought to characterize contributions of the FLI protein to overall EWS/FLI funct (open full item for complete abstract)

Committee: Stephen Lessnick MD/PhD (Advisor); Timothy Cripe MD/PhD (Committee Member); Lawrence Kirschner MD/PhD (Committee Member); Mark Parthun PhD (Committee Member) Subjects: Biomedical Research; Cellular Biology; Molecular Biology; Oncology