
RAPSYN은 BCR-ABL의 넷딜레이션을 매개하여 BCR-ABL의 안정성을 높여 필라델피아 염색체 양성 백혈병의 진행을 촉진한다.


coremsg

Philadelphia chromosome-positive (Ph+) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKI) 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.

### Competing Interest Statement

A Chinese patent application was filed with the number of 202210107464.7. China Pharmaceutical University owns the patent rights, and Y. C., Y. Y., M. Z., B. D., X. L., S. W. and X. Z. are the inventors of the patent.

RAPSYN-Mediated Neddylation of BCR-ABL Alternatively Determines the Fate of Philadelphia Chromosome-positive Leukemia

필라델피아-염색체-양성-백혈병의-rapsyn-매개-bcr-abl-넷딜레이션이-질병의-운명을-결정한다


필라델피아 염색체 양성 백혈병의 RAPSYN 매개 BCR-ABL 넷딜레이션이 질병의 운명을 결정한다
