Targeting Plek2 as a Novel Approach for the Treatment of Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are a group of bone marrow diseases with excessive myeloid cell production and increased risk of evolving to acute myeloid leukemia. V617F driver mutation of JAK2 is one of the leading causes of MPNs. The discovery of this mutation led to the development of JAK inhibitors for the treatment of MPNs. However, JAK2 inhibitors are not curative. In addition, MPN patients treated with JAK2 inhibitor often develop drug resistance and severe side effects due to the indispensable roles of JAK2 in normal blood cell development. We have been studying new approaches to treating MPNs, especially focusing on the downstream effectors of the JAK2 pathway. Our preliminary studies revealed that loss of Plek2, which is a novel downstream target of the JAK2 pathway, ameliorated JAK2V617F-induced myeloproliferative phenotypes, and more significantly reverted the widespread vascular occlusions and lethality of JAK2V617F MPN mouse model. In this proposal, we will use our newly designed small molecular Plek2 inhibitors to treat MPN mouse model and bone marrow progenitor cells from MPN patients. Successful completion of this project will lay the foundation for clinical trials of using Plek2 inhibitors as single agents or in combination with other compounds to treat MPNs.