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Boone- Final Dissertation Document.pdf (3.16 MB)

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Characterization of FET and ETS domain contributions to fusion oncoprotein activity in Ewing sarcoma

Boone, Megann A
http://rave.ohiolink.edu/etdc/view?acc_num=osu162523250959622

Abstract Details

2021, Doctor of Philosophy, Ohio State University, 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 function. Previously published data surrounding EWS/FLI function supports that the EWS domain is responsible for protein-protein interactions and transcriptional regulatory properties observed for the fusion protein. The FLI domain reportedly confers a sole function of DNA-binding to EWS/FLI activity. The vast majority of studies surrounding FLI contributions to the fusion protein were completed in alternative, non-Ewing sarcoma model systems. As new data surrounding other ETS factors have implicated regions surrounding the DNA-binding domain of the protein in modulation of overall activity, we sought to characterize regions surrounding the FLI DNA-binding domain in an appropriate Ewing sarcoma cellular model. Herein, we identify a novel role of FLI in EWS.FLI-mediated transcriptional regulation to the structural regions flanking the FLI DNA-binding domain. These structural features are critical for overall EWS/FLI protein activity and downstream oncogenesis, revealing a possible novel therapeutic vulnerability that may be utilized in drug development of targeted inhibitors in the future. Although it is widely accepted that FET/ETS fusion proteins act as oncogenic drivers of disease in Ewing sarcomagenesis, specific contributions of the FET and ETS domains to protein activity have yet to be fully elucidated. This body of work successfully determined that FET/ETS fusion proteins function similarly in Ewing sarcoma cells, and also identified a novel role of the ETS DNA-binding domain in transcriptional regulatory function of the fusion protein(s) that is required for oncogenesis. Together, these findings inform the clinical diagnosis process for Ewing sarcoma patients who present with a rare, alternative FET/ETS fusion and simultaneously identify a potential motif for FET/ETS protein inhibition that may be useful in the treatment of this aggressive disease, thus impacting patient outcomes.
Stephen Lessnick, MD/PhD (Advisor)
Timothy Cripe, MD/PhD (Committee Member)
Lawrence Kirschner, MD/PhD (Committee Member)
Mark Parthun, PhD (Committee Member)
181 p.
Biomedical Research; Cellular Biology; Molecular Biology; Oncology
Ewing sarcoma; chromosomal translocation; FET; ETS; pediatric cancer; oncology; fusion protein; EWS-FLI

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Citations

  • Boone, M. A. (2021). Characterization of FET and ETS domain contributions to fusion oncoprotein activity in Ewing sarcoma [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu162523250959622

    APA Style (7th edition)

  • Boone, Megann. Characterization of FET and ETS domain contributions to fusion oncoprotein activity in Ewing sarcoma. 2021. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu162523250959622.

    MLA Style (8th edition)

  • Boone, Megann. "Characterization of FET and ETS domain contributions to fusion oncoprotein activity in Ewing sarcoma." Doctoral dissertation, Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu162523250959622

    Chicago Manual of Style (17th edition)

osu162523250959622
199
© 2021, some rights reserved.Creative Commons License Characterization of FET and ETS domain contributions to fusion oncoprotein activity in Ewing sarcoma by Megann A Boone is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.