title: The chimeric ubiquitin ligase SH2-U-box inhibits the growth of imatinib-sensitive and resistant CML by targeting the native and T315I-mutant BCR-ABL.
abstract: Chronic myeloid leukemia (CML) is characterized by constitutively active fusion protein tyrosine kinase BCR-ABL. Although the tyrosine kinase inhibitor (TKI) against BCR-ABL, imatinib, is the first-line therapy for CML, acquired resistance almost inevitably emerges. The underlying mechanism are point mutations within the BCR-ABL gene, among which T315I is notorious because it resists to almost all currently available inhibitors. Here we took use of a previously generated chimeric ubiquitin ligase, SH2-U-box, in which SH2 from the adaptor protein Grb2 acts as a binding domain for activated BCR-ABL, while U-box from CHIP functions as an E3 ubiquitin ligase domain, so as to target the ubiquitination and degradation of both native and T315I-mutant BCR-ABL. As such, SH2-U-box significantly inhibited proliferation and induced apoptosis in CML cells harboring either the wild-type or T315I-mutant BCR-ABL (K562 or K562R), with BCR-ABL-dependent signaling pathways being repressed. Moreover, SH2-U-box worked in concert with imatinib in K562 cells. Importantly, SH2-U-box-carrying lentivirus could markedly suppress the growth of K562-xenografts in nude mice or K562R-xenografts in SCID mice, as well as that of primary CML cells. Collectively, by degrading the native and T315I-mutant BCR-ABL, the chimeric ubiquitin ligase SH2-U-box may serve as a potential therapy for both imatinib-sensitive and resistant CML.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ru
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Qinhao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.|Department of Biochemistry and Molecular Biology, Zunyi Medical College, Zunyi, Guizhou 563000, China.
authors.forename: Xiping
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
authors.forename: Daixing
authors.initials: D
authors.lastname: Zhong
authors.affiliation: Department of Pulmonary Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Ye
authors.affiliation: Department of Hematology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
authors.forename: Yuanchun
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Han
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D051380:GRB2 Adaptor Protein / Q000737:chemistry; D005822:Genetic Vectors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D020014:K562 Cells; D016086:Lentivirus / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000628:therapy*; D051379:Mice; D017354:Point Mutation; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays; D018909:src Homology Domains
chemical_list: D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D011993:Recombinant Fusion Proteins; D000068877:Imatinib Mesylate; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D016044:Fusion Proteins, bcr-abl