Journal Article

PPIL2 is a target of the JAK2/STAT5 pathway and promotes myeloproliferation via p53-mediated degradation

Sukhanova, Madina, Ji, Peng, Wang, Pan, Aydemir, Inci, Liu, Yijie, Ren, Kehan, Yang, Jing, Bi, Honghao, Han, Xu, Li, Ermin

2025

Overview

The activated JAK2/STAT pathway is characteristic of myeloproliferative neoplasms (MPNs). 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 revealed 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 MPN patients and 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 revealed PPIL2 as a critical component of the PLEK2 signalosome in driving MPN pathogenesis through negatively regulating p53, thus providing a target and an opportunity for drug repurposing by using cyclosporin A to treat MPNs.The activated JAK2/STAT pathway is characteristic of myeloproliferative neoplasms (MPNs). 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 revealed 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 MPN patients and 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 revealed PPIL2 as a critical component of the PLEK2 signalosome in driving MPN pathogenesis through negatively regulating p53, thus providing a target and an opportunity for drug repurposing by using cyclosporin A to treat MPNs.