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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\n                    <jats:sup>+<\/jats:sup>\n                    leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    leukemia.\n                  <\/jats:p>","DOI":"10.7554\/elife.88375","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T06:37:56Z","timestamp":1690526276000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.88375","source":"Crossref","is-referenced-by-count":1,"title":["RAPSYN-mediated neddylation of BCR-ABL alternatively determines the fate of Philadelphia chromosome-positive 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