title: CDKN1A-mediated responsiveness of MLL-AF4-positive acute lymphoblastic leukemia to Aurora kinase-A inhibitors.
abstract: 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 IC50 of ∼10-30 nM and displayed a phenotype of Aurora-A inhibition, whereas cells resistant to Aurora kinase inhibitors (with an IC50 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.
authors.affiliation: Division of Hematology/Oncology, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; Graduate Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Chen
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Lin
authors.forename: Jiann-Shiuh
authors.initials: JS
authors.lastname: Chen
authors.forename: Ming-Ying
authors.initials: MY
authors.lastname: Tsai
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.forename: Nai-Feng
authors.initials: NF
authors.lastname: Chen
authors.forename: Kung-Chao
authors.initials: KC
authors.lastname: Chang
authors.forename: Wen-Tsung
authors.initials: WT
authors.lastname: Huang
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Yang
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.forename: Liang-Yi
authors.initials: LY
authors.lastname: Hung
authors.forename: Tsai-Yun
authors.initials: TY
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C113855:MLL-AF4 fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051788:Myeloid-Lymphoid Leukemia Protein; D064096:Aurora Kinase A
keywords: Aurora kinase inhibitors; CDKN1A; MLL-AF4; acute lymphoblastic leukemia