The role of Plek2 in the pathogenesis of myeloproliferative neoplasms
Peng JiPhD, MD
Project Term: July 1, 2017 - June 30, 2022
Our research focuses on the study of a novel therapeutic target, named Plek2, in the development of myeloproliferative neoplasms (MPNs). MPNs can progress to leukemia and there are currently no cures. We use animal models and patient samples to study how elevated levels of Plek2 causes the disease and identify approaches to suppress the function of Plek2. Our goal is to use the knowledge from this study to develop novel therapies to treat MPNs.
Myeloproliferative neoplasms (MPNs) are a group of bone marrow diseases with overproduction of mature blood cells and increased risk of evolving to acute leukemia. A specific mutation on one of the blood cell surface proteins called Jak2 is the leading cause of this group of diseases. The discovery of this mutation led to the development of inhibitors specifically targeting Jak2. However, these inhibitors are not curative. In addition, MPN patients treated with these inhibitors often develop drug resistance and significant side effects due to the indispensable roles of this blood surface protein in normal blood production. We have been studying new approaches to treating MPNs, especially focusing on the proteins that are important for the development of MPN disease but not essential for normal blood cells. We identified one of these proteins, Plek2, which a part of normal red blood cell development but may also be involved in the disease state in some MPNs. Our studies using mouse models and tumor cell lines demonstrated that Plek2 is critical for the MPN disease development and is a mediator of Jak2 signaling. In addition, mice that lose Plek2 do not exhibit obvious side effects. These novel discoveries made Plek2 an attractive drug target for the treatment of MPNs. The overall goal of my research is to better understand how Plek2 reverts the disease progression in MPNs using mouse models and bone marrow cells from MPN patients. We will analyze how Plek2 mediates Jak2 signaling as well as how Plek2 may be involved in other MPN mutations, such as CALR and MPL. Successful completion of this project will lay the foundation for targeting Plek2 as a novel therapeutic approach for the clinical management of MPNs.