Oncotarget

Research Papers:

Depression of oncogenecity by dephosphorylating and degrading BCR-ABL

Miao Gao _, Zheng-Lan Huang, Kun Tao, Qing Xiao, Xin Wang, Wei-Xi Cao, Min Xu, Jing Hu and Wen-Li Feng

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Oncotarget. 2017; 8:3304-3314. https://doi.org/10.18632/oncotarget.13754

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Abstract

Miao Gao1,*, Zheng-Lan Huang1,*, Kun Tao2, Qing Xiao3, Xin Wang3, Wei-Xi Cao1, Min Xu1, Jing Hu1, Wen-Li Feng1

1Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by The Ministry of Education, Chongqing Medical University, Chongqing, People’s Republic of China

2Department of Immunology, Molecular Medicine and Cancer Research, Chongqing Medical University, Chongqing, People’s Republic of China

3Department 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: [email protected]

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.


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