The role of Plek2 in the pathogenesis 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 the leading cause of Philadelphia chromosome-negative MPNs. The discovery of this mutation led to the development of JAK2 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 significant side effects due to the indispensable roles of JAK2 in normal hematopoiesis. We have been studying new approaches to treating MPNs, especially focusing on the downstream effectors of the JAK2 signaling pathways. Our studies revealed that loss of Pleckstrin-2 (Plek2), which is a novel downstream target of the JAK2-STAT5 pathway, ameliorated JAK2 V617F-induced myeloproliferative phenotypes, and more significantly reverted the widespread vascular occlusions and lethality of JAK2 V617F positive MPN mouse model. In this proposal, we will validate our newly in silico designed small molecule inhibitors of Plek2 and use the validated 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 inhibitor as a single drug or in combination with other agents to treat MPNs