Abstract
To detect the expression of cancerous inhibitor of phosphatase 2A (CIP2A) in chronic myelocytic leukemia (CML) and investigate the mechanism underlying CIP2A knockdown-mediated cell proliferation and apoptosis as well as the interaction of CIP2A with breakpoint cluster region-Abelson leukemia virus (BCR-ABL). CIP2A mRNA and protein expression in chronic myelocytic leukemia-chronic (CML-CP) patients and healthy controls were determined by RT-PCR and Western blot. In vivo, c-Myc expression, PP2A activity, cell proliferation, and apoptosis of CML cells were detected with CIP2A depletion. In addition, the relationship among CIP2A, BCR-ABL, and tyrosine phosphatase SHP-1 was explored by depleting/overexpressing CIP2A or inhibiting BCR-ABL. The level of CIP2A mRNA was higher in CML-CP patients than healthy controls (56/74, 75.7 % vs. 1/35, 2.9 %, P < 0.001), and CIP2A protein was overexpressed in corresponding specimens. CIP2A knockdown by siRNA reduced the level of c-Myc protein and clonogenic formation, inhibited the activity of PP2A, K562 cell proliferation, and promoted cell apoptosis. Suppressing BCR-ABL by imatinib mesylate (IM) significantly decreased CIP2A expression. CIP2A knockdown decreased BCR-ABL but increased SHP-1 expression, and CIP2A overexpression had the reverse effect. CIP2A is overexpressed in CML-CP patients, and its expression may promote CML pathogenesis. CIP2A and BCR-ABL can regulate each other in a positive feedback loop. CIP2A may be a useful therapeutic target in CML-CP, particularly in patients with IM resistance. However, further studies are needed to validate the interaction between CIP2A and BCR-ABL using other tyrosine kinase inhibitors than IM.
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Abbreviations
- CIP2A:
-
Cancerous inhibitor of PP2A
- PP2A:
-
Protein phosphatase 2A
- S62:
-
Serine 62
- CML:
-
Chronic myelocytic leukemia
- CP:
-
Chronic phase
- IM:
-
Imatinib mesylate
- PBS:
-
Phosphate-buffered saline
- AML:
-
Acute myeloid leukemia
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Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 81170514 and 30971151), the Project Sponsored by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (The Project sponsored by SRF for ROCS, SEM), Shandong Provincial Natural Science Foundation, China (Nos. ZR2009CM002 and ZR2012HQ003), Traditional Chinese Medicine Science and Technology Development Program of Shandong Province (No. 2011-211), Colleges Science and Technology Project of Shandong Province (No. J10LF74) and the Independent Innovation Foundation of Shandong University (IIFSDU, No. 2012TS128).
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The authors have declared no conflict of interests.
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Wang, J., Huang, T., Sun, J. et al. CIP2A is overexpressed and involved in the pathogenesis of chronic myelocytic leukemia by interacting with breakpoint cluster region-Abelson leukemia virus. Med Oncol 31, 112 (2014). https://doi.org/10.1007/s12032-014-0112-7
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DOI: https://doi.org/10.1007/s12032-014-0112-7