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.