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Molecular Mechanisms of Oncogenesis & Precision Medicine University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2016 Molecular Mechanisms of Oncogenesis & Precision Medicine Approaches for Pediatric Low-Grade Gliomas Payal Jain University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Cell Biology Commons, Medicine and Health Sciences Commons, and the Molecular Biology Commons Recommended Citation Jain, Payal, "Molecular Mechanisms of Oncogenesis & Precision Medicine Approaches for Pediatric Low- Grade Gliomas" (2016). Publicly Accessible Penn Dissertations. 1782. https://repository.upenn.edu/edissertations/1782 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1782 For more information, please contact [email protected]. Molecular Mechanisms of Oncogenesis & Precision Medicine Approaches for Pediatric Low-Grade Gliomas Abstract Pediatric low-grade gliomas (PLGGs) are a heterogeneous group of tumors that collectively represent the most common childhood brain cancer. Despite favorable outcomes with surgical and adjuvant therapies, majority of patients suffer from long-term treatment-related morbidities and recurrent/inoperable disease. This necessitates a deeper understanding of PLGG biology to aid development of molecular diagnostics and low-toxicity targeted therapeutics. Hitherto, PLGGs have been defined by activating mutations that dysregulate the MAPK signaling pathway, leading to clinical testing of RAF/MAPK inhibitors for PLGGs. Interestingly, recent large-scale sequencing efforts discovered novel gene fusions in PLGGs and we identified the unique ecurrr ent association of tumor suppressor Quaking (QKI) with distinct proto-oncogenes, MYB and RAF1, in different PLGG sub- types. We hypothesized that MYB-QKI and QKI-RAF1 function via novel oncogenic mechanisms invoking a two-hit mechanism of gain-of-function in the MYB/RAF1 oncoproteins collaborating with QKI loss of putative tumor suppressor function, describing for the first time a unique gene fusion setting involving both fusion partners with implications for therapeutic targeting. Utilizing heterologous cell model systems and in vivo mouse models, we found MYB-QKI and QKI-RAF1 are capable of driving oncogenesis. Furthermore, MYB-QKI is a specific driver mutation defining angiocentric gliomas and mediates tumorigenesis via a tri-partite mechanism: (1)MYB oncogenic activation via truncation, (2)rearrangement led enhancer translocation that drives MYB-QKI expression and (3)LOH of QKI tumor suppressor. In contrast, QKI-RAF1 drives some pilocytic astrocytomas via aberrant activation of the MAPK pathway in a QKI-dimerization dependent manner. We also found differential response to RAF targeted therapy in QKI-RAF1, compared to BRAF fusions in PLGGs, due to QKI-mediated dimerization. Hence, our study highlights distinct roles for the same gene, QKI in supporting the oncogenic functions of MYB and RAF1 in different PLGG-gene fusions. Overall, our study has uncovered distinct molecular mechanisms associated with different QKI gene fusions in PLGGs. We show that MYB-QKI is specific ot angiocentric gliomas and mediates a unique oncogenic program, and with QKI-RAF1 we demonstrate how mutational context guides differential response to targeted therapy. Therefore, our study has important clinical implications on molecular diagnostics and targeted therapy for these rather understudied class of childhood brain tumors. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Adam C. Resnick Keywords Gene fusions, MYB-QKI, Pediatric brain tumor, Pediatric low-grade glioma, QKI-RAF1, Targeted therapy Subject Categories Cell Biology | Medicine and Health Sciences | Molecular Biology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/1782 MOLECULAR MECHANISMS OF ONCOGENESIS & PRECISION MEDICINE APPROACHES FOR PEDIATRIC LOW-GRADE GLIOMAS Payal Jain A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2016 Supervisor of Dissertation _____________________ Adam C. Resnick, Assistant Professor of Neurosurgery Graduate Group Chairperson ______________________ Daniel S. Kessler, Associate Professor of Cell and Developmental Biology Dissertation Committee Garrett M. Brodeur, MD, Professor of Pediatrics, Audrey E. Evans Chair in Molecular Oncology and Associate Director, Abramson Cancer Center, The Children’s Hospital of Philadelphia Margaret M. Chou, Ph.D., Associate Professor of Pathology and Laboratory Medicine Jean D. Boyer, Ph.D., Research Associate Professor of Pathology and Laboratory Medicine David B. Weiner, PhD, Professor, WW Smith Chair in Cancer Research, Director, Wistar Vaccine Center MOLECULAR MECHANISMS OF ONCOGENESIS & PRECISION MEDICINE APPROACHES FOR PEDIATRIC LOW-GRADE GLIOMAS COPYRIGHT 2016 Payal Jain This work is licensed under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 License To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-sa/3.0/us/ Dedication page To my mother, who always inspired me to pursue my dreams (Debika Jain, 69). To the children who have lost their lives to brain tumors. iii ACKNOWLEDGMENT I would like to start by thanking my dissertation mentor, Adam C. Resnick, for his unwavering commitment, never-ending enthusiasm and contagious optimism towards research and scientific collaborations for improving therapies for children with brain tumors. I will always be grateful to Adam for being a great teacher and helping me understand the most basic scientific concepts when I first started in lab. Even though I had no prior training in cancer research, Adam always believed in me and pushed me to perform to the best of my abilities. As a result of his mentorship and support, I have been able to complete two major projects within three years in his lab, could present my findings as posters and talks at major national and international conferences and most importantly, contribute in a small way to understand and possibly treat childhood brain tumors. Adam has been a truly inspirational role model, juggling many responsibilities but still always being available for his lab. No matter where I go, I truly hope to imbibe and take with me his immense dedication, hard working nature and positive and helpful attitude. Next, I would like to thank current and past lab members of the Resnick lab. I thank Katie Boucher and Namrata Choudhary for their technical help, insight and always being in lab for any help I needed in the past 3 years. I thank Harry Han for lending a helpful ear to all my lab related issues, reading all my proposal/paper drafts and always giving great scientific input. I thank Yunkaun Zhu for being a great friend and an amazing bio-informatician who always made sense of my random questions about handling big data. I thank Lucy Chong and Wanda Anselmo for being wonderful bay mates and friends, especially when working late nights in lab. I thank our past mouse technicians Amanda Silva and Aesha Vakil, and current mouse expert, Tiffany Smith for being so patient with me and helping me with my mouse experiments. I thank Angela J. Waanders for being a great mentor and supporter and the amazing female neurosurgeon, Tamara M. Fierst for being my partner-in-crime in solving the QKI-RAF1 mystery. I am lucky to have been a part of the Resnick lab, where everyone has always been extremely helpful and supportive, and it has been so much fun to celebrate birthdays, baby showers, festivals and so much more. iv I also thank our collaborators at Dana Faber Cancer Institute for their work on the MYB-QKI project. I thank Pratiti Bandopadhayay, Lori A. Ramkissoon and Guillaume Bergthold who are co-first authors on the publication and Keith L. Ligon and Rameen Beroukhim, who were co-PI’s for the project. I have learned the essence of scientific collaborations while working with the team where each contributor came forward with their expertise and made it possible for us to put together an impactful publication in Nature Genetics. Next, I am grateful for all the helpful suggestions, advice, comments and criticisms provided by my thesis committee members Garrett M. Brodeur, Margaret M. Chou, Jean D. Boyer and David B. Weiner in the past years. I thank each of them for giving me their valuable time and helping me navigate the rocky roads of graduate school. I especially thank David Weiner for being our awesome GTV Chair and always being available to listen to my problems throughout graduate school. He has truly been available for all GTV-ers and I am so grateful to have him as my Program Chair. I also thank Matthew Weitzman for being a great PI on our floor with his invaluable suggestions and scientific input and giving me his valuable time by listening to me practice talks. I am grateful to senior postdocs in the neighboring lab, Grace Tan and Mateusz Koptyra for always being available and providing me with instant solutions to any problem with my experiments/ lab-related problems/anything and everything. I am also very thankful to another group of wonderful people, who have heard me cry, complain and have celebrated every step of my graduate school journey with me- my friends. I am grateful to Montreh Tavakkoli for being my close friend and morale booster during difficult times in PhD, which
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