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

• Published in: eLife 2024-06, Vol.12
• Main Authors: Zhao, Mengya, Dai, Beiying, Li, Xiaodong, Zhang, Yixin, Qiao, Chun, Qin, Yaru, Li, Zhao, Li, Qingmei, Wang, Shuzhen, Yang, Yong, Chen, Yijun
• Format: Article
• Language: English
• Subjects: Animals; BCR-ABL protein; Biopsy; Bone marrow; Cancer; Cancer Biology; Cell Biology; Cell cycle; Cell Line, Tumor; Cytotoxicity; E. coli; Enzymes; Fusion protein; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Genetic aspects; human; Humans; Innovations; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Ligases; Malignancy; Mice; mouse; Mutation; NEDD8 Protein - genetics; NEDD8 Protein - metabolism; Patients; Philadelphia chromosome; Proteins; Rapsyn; Scientific equipment and supplies industry; Tumors; Tyrosine; Tyrosine kinase inhibitors; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.88375

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 degraders, depletion of RAPSYN expression, or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph leukemia.