title: Depression of oncogenecity by dephosphorylating and degrading BCR-ABL.
abstract: Aberrant phosphorylation and overexpression of BCR-ABL fusion protein are responsible for the main pathogenesis in chronic myeloid leukemia (CML). Phosphorylated BCR-ABL Y177 recruits GRB2 adaptor and triggers leukemic RAS-MAPK and PI3K-AKT signals. In this study, we engineered a SPOA system to dephosphorylate and degrade BCR-ABL by targeting BCR-ABL Y177. We tested its effect on BCR-ABL phosphorylation and expression, as well as cell proliferation and apoptosis in CML cells. We found that SPOA remarkably dephosphorylated BCR-ABL Y177, prevented GRB2 recruitment, and uncoupled RAS-MAPK and PI3K-AKT signals. Meanwhile, SPOA degraded BCR-ABL oncoprotein in ubiquitin-independent manner and depressed the signal transduction of STAT5 and CRKL by BCR-ABL. Furthermore, SPOA inhibited proliferation and induced apoptosis in CML cells and depressed the oncogenecity of K562 cells in mice. These results provide evidence that dephosphorylating and degrading oncogenic BCR-ABL offer an alternative CML therapy.
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by The Ministry of Education, Chongqing Medical University, Chongqing, People's Republic of China.
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, People's Republic of China.
authors.forename: Zheng-Lan
authors.initials: ZL
authors.lastname: Huang
authors.affiliation: Department of Immunology, Molecular Medicine and Cancer Research, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Kun
authors.initials: K
authors.lastname: Tao
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by The Ministry of Education, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Wei-Xi
authors.initials: WX
authors.lastname: Cao
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by The Ministry of Education, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by The Ministry of Education, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by The Ministry of Education, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Feng
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D015398:Signal Transduction; D025801:Ubiquitin
chemical_list: D025801:Ubiquitin; D016044:Fusion Proteins, bcr-abl; D046988:Proteasome Endopeptidase Complex
keywords: BCR-ABL; Y177; chronic myeloid leukemia; ornithine decarboxylase; protein tyrosine phosphatase