Science and Research

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

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-naive cells and were not observed in cells, which were resistant to various imatinib-concentrations (0.1 muM to 2 muM). Further analysis in treatment-naive 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 muM 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.

  • Kaehler, M.
  • Ruemenapp, J.
  • Gonnermann, D.
  • Nagel, I.
  • Bruhn, O.
  • Haenisch, S.
  • Ammerpohl, O.
  • Wesch, D.
  • Cascorbi, I.
  • Bruckmueller, H.

Keywords

  • Abcg2
  • drug resistance
  • drug transporters
  • methylation
  • miR-212
Publication details
DOI: 10.18632/oncotarget.21272
Journal: Oncotarget
Pages: 92018-92031 
Number: 54
Work Type: Original
Location: Assoziierter Partner, ARCN
Disease Area: LC
Partner / Member: UKSH (Kiel)
Access-Number: 29190894
See publication on PubMed

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