MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells
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Meike Kaehler1, Johanna Ruemenapp1, Daniel Gonnermann2, Inga Nagel1, Oliver Bruhn1, Sierk Haenisch1, Ole Ammerpohl3, Daniela Wesch2, Ingolf Cascorbi1 and Henrike Bruckmueller1
1Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
2Institute of Immunology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
3Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
Ingolf Cascorbi, email: [email protected]
Keywords: drug resistance, drug transporters, ABCG2, miR-212, methylation
Received: June 03, 2017 Accepted: September 08, 2017 Published: September 26, 2017
BCR-ABL-independent resistance against tyrosine kinase inhibitor is an emerging problem in therapy of chronic myeloid leukemia. Such drug resistance can be linked to dysregulation of ATP-binding cassette (ABC)-transporters leading to increased tyrosine kinase inhibitor efflux, potentially caused by changes in microRNA expression or DNA-methylation. In an in vitro-imatinib-resistance model using K-562 cells, microRNA-212 was found to be dysregulated and inversely correlated to ABC-transporter ABCG2 expression, targeting its 3’-UTR. However, the functional impact on drug sensitivity remained unknown. Therefore, we performed transfection experiments using microRNA-mimics and –inhibitors and investigated their effect on imatinib-susceptibility in sensitive and resistant leukemic cell lines. Under imatinib-treatment, miR-212 inhibition led to enhanced cell viability (p = 0.01), reduced apoptosis (p = 0.01) and cytotoxicity (p = 0.03). These effects were limited to treatment-naïve cells and were not observed in cells, which were resistant to various imatinib-concentrations (0.1 μM to 2 μM). Further analysis in treatment-naïve cells revealed that miR-212 inhibition resulted in ABCG2 upregulation and increased ABCG2-dependent efflux. Furthermore, we observed miR-212 promoter hypermethylation in 0.5 and 2 μM IM-resistant sublines, whereas ABCG2 methylation status was not altered. Taken together, the miR-212/ABCG2-axis influences imatinib-susceptibility contributing to development of imatinib-resistance. Our data reveal new insights into mechanisms initiating imatinib-resistance in leukemic cells.
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