Background: The prognosis of patients with relapsed or resistant acute lymphoblastic leukemia (ALL) is quite poor, and resistance to chemotherapy in ALL cells remains a challenge to successful treatment. Overexpression of Aurora kinases is largely observed in many cancers, including hematologic malignancies. Aurora kinases have become attractive therapeutic targets to help overcome chemotherapy resistance. Methods: The expression of Aurora kinases and their activators was analyzed by Western blot analysis. Drug susceptibility was determined by MTT assay. Expression of CDKN1A was detected by Western blot and Q-PCR. The status of TP53 in ALL cells was determined by Sanger sequencing. Results: Nine ALL cell lines exhibited different susceptibilities to Aurora kinase inhibitors (AKIs). Cells sensitive to AKIs underwent apoptosis at an IC50 of approximately 10 to 30nM and displayed a phenotype of Aurora-A inhibition, whereas cells resistant to Aurora kinase inhibitors (with an IC50 more than 10 mM) accumulated polyploidy, which may have resulted from Aurora-B inhibition. Drug susceptibility was not correlated with the expression level or activation status of Aurora kinases. RS4;11 and MV4;11 cells, which contain the MLL-AF4 gene, were both sensitive to Aurora-A inhibitors. CDKN1A might govern the drug responsiveness of ALL cell lines in a TP53-independent manner. Primary ALL cells with MLL-AF4 and CDKN1A expression were sensitive to AKIs. Conclusions: Our study suggests that Aurora-A kinase inhibitors may have clinical utility in MLL-AF4-positive ALL. CDKN1A can be used as a biomarker to determine drug responsiveness in MLL-AF4-positive ALL.
Date:
2014-11
Relation:
European Journal of Cancer. 2014 Nov;50(Suppl. 6):19-20.
