title: Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells.
abstract: The gradual emerging of resistance to imatinib urgently calls for the development of new therapy for chronic myeloid leukemia (CML). The fusion protein Bcr-Abl, which promotes the malignant transformation of CML cells, is mainly located in the cytoplasm, while the c-Abl protein which is expressed in the nucleus can induce apoptosis. Based on the hetero-dimerization of FKBP (the 12-kDa FK506- and rapamycin-binding protein) and FRB (the FKBP-rapamycin binding domain of the protein kinase, mTOR) mediated by AP21967, we constructed a nuclear transport system to induce cytoplasmic Bcr-Abl into nuclear. In this study, we reported the construction of the nuclear transport system, and we demonstrated that FN3R (three nuclear localization signals were fused to FRBT2098L with a FLAG tag), HF2S (two FKBP domains were in tandem and fused to the SH2 domain of Grb2 with an HA tag) and Bcr-Abl form a complexus upon AP21967. Bcr-Abl was imported into the nucleus successfully by the nuclear transport system. The nuclear transport system inhibited CML cell proliferation through mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (STAT5) pathways mainly by HF2S. It was proven that nuclear located Bcr-Abl induced CML cell (including imatinib-resistant K562G01 cells) apoptosis by activation of p73 and its downstream molecules. In summary, our study provides a new targeted therapy for the CML patients even with Tyrosine Kinase Inhibitor (TKI)-resistance.
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China. lqianyincqmu@163.com.
authors.forename: Qianyin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China. zhenglan_2@163.com.
authors.forename: Zhenglan
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China. gaomiao_1@163.com.
authors.forename: Miao
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China. weixicqmu@163.com.
authors.forename: Weixi
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Xiaoqincqmufyy@163.com.
authors.forename: Qin
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China. luohongweicqmu@163.com.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China. fengwlcqmu@sina.com.
authors.forename: Wenli
authors.initials: W
authors.lastname: Feng
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019913:Nuclear Localization Signals / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D050799:STAT5 Transcription Factor / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D014443:Tyrosine / Q000037:antagonists & inhibitors*
chemical_list: C539629:AP 21967; D019913:Nuclear Localization Signals; D050799:STAT5 Transcription Factor; D014443:Tyrosine; D016044:Fusion Proteins, bcr-abl; D020123:Sirolimus
keywords: Bcr-Abl; apoptosis; nuclear; proliferation; transport