RAPSYN-mediated neddylation of BCR-ABL alternatively determines the fate of Philadelphia chromosome-positive leukemia.

ABSTRACT: Philadelphia chromosome-positive (Ph⁺) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved remarkable success in prolonging patient survival, intolerance, relapse, and TKI resistance remain serious issues for patients with Ph⁺ leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph⁺ leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast to in vivo ineffectiveness of PROTAC-based degra

SUBMITTER: Zhao M 

PROVIDER: S-EPMC11168747 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature