Oncotarget

Research Papers:

MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells

Meike Kaehler, Johanna Ruemenapp, Daniel Gonnermann, Inga Nagel, Oliver Bruhn, Sierk Haenisch, Ole Ammerpohl, Daniela Wesch, Ingolf Cascorbi _ and Henrike Bruckmueller

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2017; 8:92018-92031. https://doi.org/10.18632/oncotarget.21272

Metrics: PDF 1256 views  |   HTML 3133 views  |   ?  


Abstract

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

Correspondence to:

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

ABSTRACT

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 21272