This project aims to elucidate the mechanism of action of the proto-oncogene SETBP1 (SET-binding protein 1) through analysis of functional domains and cell cycle markers (Aim 1), and to use this mechanistic data to identify novel therapeutic targets (Aim 2). To elucidate the role of functional domains in SETBP1-driven leukemia and cell proliferation, I will mutate these domains and test the ability of the perturbed constructs to promote the leukemic phenotype in a hematopoietic colony forming unit assay and in vivo. I will also utilize targeted gene expression analysis to understand how cell cycle regulators are perturbed in context of these functional domain mutations. I propose to use our new mechanistic data and preliminary small molecule functional screening data to conduct informed drug development in cell line models and patient samples. I will validate prospective drug targets and combinations in a novel SETBP1-mutant CNL cell line model, and then assess the efficacy of the best agents in patient samples using one of the largest repositories of CNL samples in the world. The proposed project takes advantage of my expertise in in vitro and in vivo modelling, while affording me the opportunity to develop new skills and a fundamental understanding of translational cancer biology. Regular input from my co-sponsors and other cancer biologists at OHSU will provide me with critical feedback on my data and generate ideas for innovative experiments. Dr. Maxson is a leading expert on the biology of CNL and mechanisms of CSF3R-driven oncogenesis. She has substantial experience with cellular and molecular biology techniques and investigating novel oncogenic mutations in leukemia, making her ideally suited to mentor me on this project. My co-sponsor, Dr. Brian Druker, is a physician scientist and the director of the Knight Cancer Institute. As a physician scientist and a pioneer of targeted cancer therapy, Dr. Druker can provide clinical context for my work and help to ensure that I am addressing the most clinically relevant questions. Dr. Druker?s wealth of expertise in therapeutic development is essential for Aim 2 of this proposal.
SETBP1 (SET-binding protein 1) mutations are an independent predictors of reduced overall patient survival in Chronic Neutrophilic Leukemia (CNL), a rare but well-defined myeloid leukemia. I will investigate the mechanism of action of SETBP1 through analysis of functional domains and cell cycle regulation, and to use this mechanistic data to identify novel therapeutic targets. Studying SETBP1 mutations in the context of CNL will help us understand the mechanisms of myeloid leukemia progression, transforming this marker of poor prognosis into an opportunity for targeted therapeutics.
