Proteomic-based identification of Apg-2 as a therapeutic target for chronic myeloid leukemia |
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Authors: | Yajuan Li Xi Chen Meng Shi Haixia Wang Weixi Cao Xiaozhong Wang Chunli Li Wenli Feng |
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Institution: | Department of Clinical Hematology, Key Laboratory of the Laboratory of Medical Diagnostics of the Ministry of Education, Chongqing Medical University, Chongqing 400016, PR China |
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Abstract: | The oncogenic BCR/ABL tyrosine kinase induces constitutive enhanced “spontaneous” DNA damage and unfaithful repair in Philadelphia chromosome positive leukemia cells. Here, we investigated the changes of protein profile in H2O2-induced DNA damage/repair in BaF3-MIGR1 and BaF3-BCR/ABL cells through a proteomic strategy consisting of two-dimensional gel electrophoresis (2-DE) coupled with MALDI-TOF mass spectrometry. In total, 41 spots were differentially expressed and 13 proteins were identified with further MS analysis. Two essential proteins, Proto-oncogene tyrosine–protein kinase ABL1 (c-ABL) and Heat shock 70 kDa protein 4 (Apg-2), were confirmed by Western blot and showed consistent changes with proteomic results. Moreover, functional analysis demonstrated that inhibition of Apg-2 not only decreased cell proliferation, but also induced cell apoptosis in BCR/ABL positive cells (BaF3-BCR/ABL, BaF3-BCR/ABLT315I). We also proved that Apg-2 inhibition aggravated H2O2 induced damage in BCR/ABL positive cells, and enhanced the sensitivity of BaF3-BCR/ABLT315I to STI571. Taken together, the findings in this work provide us with some clues to a better understanding of the molecular mechanisms underlying BCR/ABL in the DNA damage/repair processes and demonstrated that Apg-2 would be a valid target for anti-leukemia drug development. |
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