Abstract
The activated JAK2/STAT pathway is characteristic of myeloproliferative neoplasms (MPNs). The pleckstrin 2 (PLEK2) signalosome is downstream of the JAK2/STAT5 pathway and plays an important role in MPN development. The detailed molecular composition of this signalosome is unclear. Here, we reveal peptidylprolyl isomerase-like 2 (PPIL2) as a critical component of the complex in regulating human and murine erythropoiesis. PPIL2 was a direct target of STAT5 and was upregulated in patients with MPN and in a Jak2V617F MPN mouse model. Mechanistically, PPIL2 interacted with and catalyzed p53 polyubiquitination and proteasome-mediated degradation to promote cell growth. Ppil2 deficiency, or inhibition by cyclosporin A, led to a marked upregulation of p53 in vivo and ameliorated myeloproliferative phenotypes in Jak2V617F mice. Cyclosporin A also markedly reduced JAK2-mutated erythroid and myeloid proliferation in an induced pluripotent stem cell-derived human bone marrow organoid model. Our findings reveal PPIL2 as a critical component of the PLEK2 signalosome in driving MPN pathogenesis through negative regulation of p53, thus providing a target and opportunity for drug repurposing using cyclosporin A to treat MPNs.