title: ABL SH3 mutant inhibits BCR-ABL activity and increases imatinib sensitivity by targeting RIN1 protein in CML cell.
abstract: SH3 domain plays an important role in maintaining autoinhibition of BCR-ABL protein. RIN1 interacts with BCR-ABL SH3 domain via PxxP motifs to promote autophosphorylation as well as activation of BCR-ABL tyrosine kinase, suggesting using exogenous SH3 domain which blocks the interaction of BCR-ABL and RIN1 could be an adjunct therapy for CML. Here, we reported a novel p-BCR-ABL inhibitor, designed as ABL SH3 mutant, and identified its effects on inhibiting the tyrosine kinase activity of BCR-ABL without or with imatinib (IM) in vitro and in vivo. Our results demonstrated that ABL SH3 mutant T79Y markedly repressed the expression of BCR-ABL signaling pathways in IM-resistant cell lines KCL22 and K562/G01 as well as IM-sensitive cell line K562. Moreover, combination of T79Y with IM considerably decreased the proliferation of leukemia cells in vivo. Inhibition of BCR-ABL and RIN1 interaction using exogenous modified BCR-ABL SH3 domain provides a feasible and alternative option of small molecule inhibitors for CML treatment.
authors: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
authors: Xin
authors: X
authors: Liu
authors: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
authors: Yajuan
authors: Y
authors: Li
authors: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
authors: Liangxue
authors: L
authors: Wen
authors: Department of Immunology, Molecular Medicine and Cancer Research, Chongqing Medical University, Chongqing 400016, China.
authors: Kun
authors: K
authors: Tao
authors: Department of Hematology, The First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China.
authors: Qing
authors: Q
authors: Xiao
authors: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
authors: Weixi
authors: W
authors: Cao
authors: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
authors: Zhenglan
authors: Z
authors: Huang
authors: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
authors: Miao
authors: M
authors: Gao
authors: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
authors: Hui
authors: H
authors: Li
authors: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
authors: Fang
authors: F
authors: Wang
authors: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China. Electronic address: fengwlcqmu@sina.com.
authors: Wenli
authors: W
authors: Feng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D018909:src Homology Domains
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; C092117:RIN1 protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: BCR-ABL; Chronic myeloid leukemia; RIN1; SH3 domain