Depression of oncogenecity by dephosphorylating and degrading BCR-ABL.

// Miao Gao 1, * , Zheng-Lan Huang 1, * , Kun Tao 2 , Qing Xiao 3 , Xin Wang 3 , Wei-Xi Cao 1 , Min Xu 1 , Jing Hu 1 , Wen-Li Feng 1 1 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 2 Department of Immunology, Molecular Medicine and Cancer Research, Chongqing Medical University, Chongqing, People’s Republic of China 3 Department of Hematology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Wen-Li Feng, email: fengwlcqmu@sina.com Keywords: chronic myeloid leukemia, BCR-ABL, Y177, protein tyrosine phosphatase, ornithine decarboxylase Received: April 30, 2016      Accepted: November 21, 2016      Published: December 01, 2016 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.