PPIL2 is a target of the JAK2/STAT5 pathway and promotes myeloproliferation via degradation of p53
Year: 2025
Type: article
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.
DOI: 10.1172/jci181394
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Awards: The roles of mDia2 in hematopoietic stem and progenitor cell engraftment and migration, G2630007612, G2697955228, The roles of mDia2 in membrane remodeling and organelle clearance during reticulocyte formation, The functional role of DDX41 in myelodysplastic syndromes, G431131125, G4571580823, G4903433812, G502122084, G5779630252, G581773441, Functional roles of DDX41 in the homeostasis of G quadruplexes in erythropoiesis
OpenAlex ID: W4410192591