The Role of EZH2 in Lymphomagenesis
Abstract
My research interests involve understanding mechanisms of disrupted gene expression in cancer and the design of rational treatment strategies. I have acquired a strong foundation in genetics and molecular biology from my undergraduate studies at Cornell University as well as from my time as a research technician at Weill Cornell. As a PhD student, my current training objectives are focused on expanding my expertise in computational biology. This will facilitate an integrative, systems-wide approach to utilize state of the art approaches and connect complex changes in the behavior of genes to cell biology and cancer. The Horizon Award will advance my career in lymphoma and cancer systems biology research from both a basic and translational perspective. It will provide me with funding opportunities to investigate how a frequent but poorly understood mutation drives the disease at both a molecular and physiological level and will therefore provide contexts for the use of novel therapeutic strategies. To guide my research and training efforts, I appropriately sought the co-mentorship of Drs. Olivier Elemento and Ari Melnick, who are leaders in the field of cancer systems biology and lymphoma research. They have worked together on over 26 joint publications and have co-mentored 7 students and post-docs within the past 9 years. In addition to their direct mentorship and support of my research, my training will also incorporate additional courses in advanced computational genomics and machine learning, including courses offered by Cold Spring Harbor Laboratory and Cornell Tech. To gain additional feedback and support, I will also attend and submit abstracts to the American Society of Hematology and the American Association for Cancer Research annual meetings. The Horizon Award will help to cover the costs incurred from attending these conferences and courses. Collectively, my academic training, previous research experiences, and current research environment will enable me to accomplish the objectives set forth in the proposed plan and support my long-term career goal of being a leader at the forefront of systems biology research in cancer. The proposed research has significant applicability in the development of novel therapeutic approaches, because it involves investigating a poorly understood but highly frequent mutation of a catalytic protein, Enhancer of zeste homolog 2 (EZH2). EZH2 is highly expressed and mutated in approximately 25% of the two most common subtypes of non-Hodgkin’s Lymphoma (NHL), follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL). EZH2’s mechanism has been elusive and nearly paradoxical to date. It was initially described as a loss-of-function mutation where the protein was thought to be inactivated. Yet follow-up experiments confirmed it to have an enhanced capability in certain contexts. My preliminary work characterizes the system-wide implications of this dual effect by utilizing both experimental and computational methods. The objectives of this proposal are to define the precise mechanisms through which mutant EZH2 promotes cancer development and understand their implications broadly throughout cell biology. This will allow us to investigate novel therapeutic approaches by rationally targeting a combination of mechanisms relevant and necessary for disease transformation. Additionally, this protein has been shown to be dysregulated in many other cancers, including prostate, breast, lung, and others. The finding of this work could lead to repositioning of these drugs to many different contexts of disease and has the potential to be immensely impactful. Non-Hodgkin’s Lymphoma is a known occupational disease and has been associated with occupational exposure to solvents, such as benzene, pesticides, disease fuel, and other environmental risk factors relevant to military personnel. It is the seventh most common cancer in the U.S and those in active duty working with these agents
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010478
Entities
People
- Dylan Mcnally
Organizations
- United States Army
- Weill Cornell Medicine