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

作者：Mengya Zhao, Beiying Dai, Xiaodong Li, Yixin Zhang, Chun Qiao, Yaru Qin, Li Zhao, Qingmei Li, Shuzhen Wang, Yong Yang, Yijun Chen · 发表于：eLife · 年份：2024 · DOI：10.7554/elife.88375.3 · 被引用次数：4 · 研究领域：Protein Degradation and Inhibitors、Multiple Myeloma Research and Treatments、Peptidase Inhibition and Analysis

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.