CIP2A is overexpressed and involved in the pathogenesis of chronic myelocytic leukemia by interacting with breakpoint cluster region-Abelson leukemia virus

• Published in: Medical oncology (Northwood, London, England) Vol. 31; no. 8; p. 112
• Main Authors: Wang, Juandong, Huang, Tao, Sun, Jianzhi, Yu, Yuan, Liu, Zhifang, Li, Wenjuan, Jia, Jihui, Chen, Chunyan
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.08.2014; Springer Nature B.V
• Subjects: Adult; Aged; Apoptosis - genetics; Autoantigens - genetics; Autoantigens - metabolism; Benzamides - pharmacology; Case-Control Studies; Cell Proliferation - genetics; Female; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Gene Expression Regulation, Leukemic; Gene Knockdown Techniques; Hematology; Humans; Imatinib Mesylate; Internal Medicine; K562 Cells - drug effects; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Male; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Middle Aged; Oncology; Original Paper; Pathology; Piperazines - pharmacology; Proto-Oncogene Proteins c-myc - genetics; Pyrimidines - pharmacology; Young Adult; CIP2A; Proliferation; Chronic myelocytic leukemia; Apoptosis
• ISSN: 1357-0560; 1559-131X
• DOI: 10.1007/s12032-014-0112-7

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.