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.

Abnormal modification in protein Neddylation is closely related to the occurrence and progression of various tumors. Studies have shown that the level of enzymes participating in Neddylation is higher than that in normal neighboring tissues, so the relationship between Neddylation and cancer has aroused much concern. Neddylation has been considered to be a novel anticancer target. Neddylation inactivation by a first-in-class small molecular inhibitor, MLN4924, induces cell cycle arrest, apoptosis, senescence and autophagy in different tumor cells. MLN4924 also exerts significant anticancer effects by inhibiting tumor angiogenesis and regulating the function of immune cells. In this review, the latest progress of protein Neddylation and tumor cell cycle, apoptosis, senescence, autophagy, angiogenesis and regulation of immunocyte were briefly introduced to provide theoretical reference for the development of antitumor drugs targeting Neddylation.