Intrinsic and Extrinsic FactorsDriving Clonal Evolution and Disease Progression in Myeloproliferative Neoplasms

About This Grant

PROJECT SUMMARY – OVERALL This Program Project Grant (PPG) seeks to address critical gaps in our current understanding of the pathogenesis of myeloproliferative neoplasms (MPNs). The overall objective of this proposal is to determine how inflammatory cytokine signaling pathways intersect with cell intrinsic/extrinsic mechanisms to drive clonal expansion and MPN disease progression. Our proposed PPG comprises four Projects and three Cores. Each of the Projects are led by an established investigator with many years of experience in their respective field of research. Despite this being a new PPG application, the Project Leaders already have a history of collaborating and publishing together, with many jointly authored publications. The proposed projects leverage established collaborations and incorporate state-of-the-art approaches to foster synergy beyond what could be achieved independently. Project 1 investigates mechanisms of DUSP6-RSK1 signaling driving MPN progression. Project 2 is focused on cell extrinsic mechanisms influencing MPN clonal evolution. Project 3 studies non-cell-intrinsic mechanisms of JAK2- mutant HSC clonal expansion. Project 4 is focused on the role of TNFɑ in MPN disease development and clonal expansion. Core A is the Administrative Core that will execute the overall PPG objectives, ensuring that all research and programmatic goals are met. Core B is the Biospecimen and Pathology Core that will centrally manage sample collection, processing and storage, and will coordinate the integration of de-identified clinical data with individual MPN patients and samples. Core C is the Bioinformatics and Biostatistics Core will provide essential bioinformatics and biostatistical expertise to support the analytical needs of all projects within the PPG. All Project Leaders and Core Leaders are at the same institution, reflecting the exceptional scientific environment at Washington University that will further enhance the impact of this PPG.