The activated JAK2-STAT pathway is characteristic of myeloproliferative neoplasms (MPNs). We previously revealed that Plek2, a downstream target of the JAK2/STAT5 pathway, functions as a scaffold protein to activate Akt and plays an important role in the pathogenesis of JAK2 V617F-induced MPNs. To further explore the mechanisms of the Plek2 signalosome, we performed a comprehensive proteomic analysis of Plek2 interacting proteins and found peptidylprolyl isomerase-like 2 (PPIL2) as a potential novel effector of the signalosome. As a U-box E3 ubiquitin ligase, PPIL2 was reported to be involved in cancer metastasis. However, its role in normal and malignant hematopoiesis remains unknown. We found that PPIL2 is required for human and murine erythropoiesis in vitro. Knockout of PPIL2 through CRISPR/Cas9 significantly reduced cell proliferation and differentiation and led to marked apoptosis. Mechanistically, PPIL2 interacts with and catalyzes p53 polyubiquitination at lysine 24 to promote proteosome-mediated p53 degradation, thereby preventing p53-dependent cell cycle inhibition and apoptosis. We further revealed that PPIL2 is a downstream target of the JAK2/STAT5 pathway and is upregulated in a JAK2 V617F-positive MPN mouse model and in patients with MPNs. Loss of Ppil2 ameliorated JAK2 V617F-induced myeloproliferative phenotypes including erythrocytosis, neutrophilia, thrombocytosis, and splenomegaly in JAK2 V617F-knockin mice. The same findings were also observed when the JAK2 V617F-knockin mice were treated with cyclosporin A, an inhibitor of PPIL2. Our findings reveal PPIL2 as an effector of the JAK2/STAT5 pathway and Plek2 signalosome. PPIL2 plays an important role in normal erythropoiesis and the pathogenesis of JAK2 V617F-induced MPNs by degrading p53, pointing to PPIL2 as a potential therapeutic target for the treatment of MPNs.
Disclosures
No relevant conflicts of interest to declare.
