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Our previous study reported that a synthetic steroidal glycoside SBF\u20101 showed remarkable anti\u2010CML activity by inducing the degradation of native Bcr\u2010Abl1 protein. Here, we observed the comparable growth inhibition for SBF\u20101 in CML cells harboring T315I mutant Bcr\u2010Abl1 in vitro and in vivo. SBF\u20101 triggered its degradation through disrupting the interaction between protein\u2010tyrosine phosphatase 1B (PTP1B) and Bcr\u2010Abl1. Using SBF\u20101 as a tool, we found that Tyr46 in the PTP1B catalytic domain and Tyr852 in the Bcr\u2010Abl1 pleckstrin\u2010homology (PH) domain are critical for their interaction. Moreover, the phosphorylation of Tyr1086 within the Bcr\u2010Abl1 SH2 domain recruited the E3 ubiquitin ligase c\u2010Cbl to catalyze K27\u2010linked ubiquitin chains, which serve as a recognition signal for p62\u2010dependent autophagic degradation. PTP1B dephosphorylated Bcr\u2010Abl1 at Tyr1086 and prevented the recruitment of c\u2010Cbl, leading to the stability of Bcr\u2010Abl1. This study unravels the action mechanism of PTP1B in stabilizing Bcr\u2010Abl1 protein and indicates that the PTP1B\u2010Bcr\u2010Abl1 interaction might be one of druggable targets for TKI\u2010resistant CML with point mutations.<\/jats:p>","DOI":"10.1111\/cas.15580","type":"journal-article","created":{"date-parts":[[2022,9,10]],"date-time":"2022-09-10T09:58:15Z","timestamp":1662803895000},"page":"247-258","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeting the <scp>PTP1B\u2010Bcr\u2010Abl1<\/scp> interaction for the degradation of <scp>T315I<\/scp> mutant <scp>Bcr\u2010Abl1<\/scp> in chronic myeloid leukemia"],"prefix":"10.1111","volume":"114","author":[{"given":"Ahmed","family":"Elgehama","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences Nanjing University  Nanjing 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