Laboratory of Chemical Biology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
Beiying Dai
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
Xiaodong Li
Laboratory of Chemical Biology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
Yixin Zhang
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
Chun Qiao
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
Yaru Qin
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
Zhao Li
Laboratory of Chemical Biology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
Qingmei Li
Laboratory of Chemical Biology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
Laboratory of Chemical Biology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; Chongqing Innovation Institute of China Pharmaceutical University, Chongqing, China
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.
