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CDKN1A‐mediated responsiveness of MLL‐AF4 ‐positive acute lymphoblastic leukemia to Aurora kinase‐A inhibitors
Author(s) -
Chen YaPing,
Lin HuiJu,
Chen JiannShiuh,
Tsai MingYing,
Hsieh HsingPang,
Chang JangYang,
Chen NaiFeng,
Chang KungChao,
Huang WenTsung,
Su WuChou,
Yang ShuTing,
Chang WenChang,
Hung LiangYi,
Chen TsaiYun
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28708
Subject(s) - aurora inhibitor , aurora kinase , aurora b kinase , kinase , aurora a kinase , cancer research , cell culture , biology , microbiology and biotechnology , apoptosis , cell , cell cycle , biochemistry , cell division , genetics , cytokinesis
Overexpression of Aurora kinases is largely observed in many cancers, including hematologic malignancies. In this study, we investigated the effects and molecular mechanisms of Aurora kinase inhibitors in acute lymphoblastic leukemia (ALL). Western blot analysis showed that both Aurora‐A and Aurora‐B are overexpressed in ALL cell lines and primary ALL cells. Both VE‐465 and VX‐680 effectively inhibited Aurora kinase activities in nine ALL cell lines, which exhibited different susceptibilities to the inhibitors. Cells sensitive to Aurora kinase inhibitors underwent apoptosis at an IC 50 of ∼10–30 nM and displayed a phenotype of Aurora‐A inhibition, whereas cells resistant to Aurora kinase inhibitors (with an IC 50 more than 10 μM) accumulated polyploidy, which may have resulted from Aurora‐B inhibition. Drug susceptibility of ALL cell lines was not correlated with the expression level or activation status of Aurora kinases. Interestingly, RS4;11 and MV4;11 cells, which contain the MLL‐AF4 gene, were both sensitive to Aurora kinase‐A inhibitors treatment. Complementary DNA (cDNA) microarray analysis suggested that CDKN1A might govern the drug responsiveness of ALL cell lines in a TP53‐independent manner. Most importantly, primary ALL cells with MLL‐AF4 and CDKN1A expression were sensitive to Aurora kinase inhibitors. Our study suggests CDKN1A could be a potential biomarker in determining the drug responsiveness of Aurora kinase inhibitors in ALL, particularly in MLL‐AF4 ‐positive patients.