Open Access

Genome‑wide expression and methylation analyses reveal aberrant cell adhesion signaling in tyrosine kinase inhibitor‑resistant CML cells

  • Authors:
    • Meike Kaehler
    • Merit Litterst
    • Julia Kolarova
    • Ruwen Böhm
    • Henrike Bruckmueller
    • Ole Ammerpohl
    • Ingolf Cascorbi
    • Inga Nagel
  • View Affiliations

  • Published online on: June 22, 2022     https://doi.org/10.3892/or.2022.8355
  • Article Number: 144
  • Copyright: © Kaehler et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Although chronic myeloid leukemia (CML) can be effectively treated using BCR‑ABL1 kinase inhibitors, resistance due to kinase alterations or to BCR‑ABL1 independent mechanisms remain a therapeutic challenge. For the latter, the underlying mechanisms are widely discussed; for instance, gene expression changes, epigenetic factors and alternative signaling pathway activation. In the present study, in vitro‑CML cell models of resistance against the tyrosine kinase inhibitors (TKIs) imatinib (0.5 and 2 µM) and nilotinib (0.1 µM) with biological replicates were generated to identify novel mechanisms of resistance. Subsequently, genome‑wide mRNA expression and DNA methylation were analyzed. While mRNA expression patterns differed largely between biological replicates, there was an overlap of 71 genes differentially expressed between cells resistant against imatinib or nilotinib. Moreover, all TKI resistant cell lines demonstrated a slight hypermethylation compared with native cells. In a combined analysis of 151 genes differentially expressed in the biological replicates of imatinib resistance, cell adhesion signaling, in particular the cellular matrix protein fibronectin 1 (FN1), was significantly dysregulated. This gene was also downregulated in nilotinib resistance. Further analyses showed significant FN1‑downregulation in imatinib resistance on mRNA (P<0.001) and protein level (P<0.001). SiRNA‑mediated FN1‑knockdown in native cells reduced cell adhesion (P=0.02), decreased imatinib susceptibility visible by higher Ki‑67 expression (1.5‑fold, P=0.04) and increased cell number (1.5‑fold, P=0.03). Vice versa, recovery of FN1‑expression in imatinib resistant cells was sufficient to partially restore the response to imatinib. Overall, these results suggested a role of cell adhesion signaling and fibronectin 1 in TKI resistant CML and a potential target for novel strategies in treatment of resistant CML.
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August-2022
Volume 48 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Kaehler M, Litterst M, Kolarova J, Böhm R, Bruckmueller H, Ammerpohl O, Cascorbi I and Nagel I: Genome‑wide expression and methylation analyses reveal aberrant cell adhesion signaling in tyrosine kinase inhibitor‑resistant CML cells. Oncol Rep 48: 144, 2022
APA
Kaehler, M., Litterst, M., Kolarova, J., Böhm, R., Bruckmueller, H., Ammerpohl, O. ... Nagel, I. (2022). Genome‑wide expression and methylation analyses reveal aberrant cell adhesion signaling in tyrosine kinase inhibitor‑resistant CML cells. Oncology Reports, 48, 144. https://doi.org/10.3892/or.2022.8355
MLA
Kaehler, M., Litterst, M., Kolarova, J., Böhm, R., Bruckmueller, H., Ammerpohl, O., Cascorbi, I., Nagel, I."Genome‑wide expression and methylation analyses reveal aberrant cell adhesion signaling in tyrosine kinase inhibitor‑resistant CML cells". Oncology Reports 48.2 (2022): 144.
Chicago
Kaehler, M., Litterst, M., Kolarova, J., Böhm, R., Bruckmueller, H., Ammerpohl, O., Cascorbi, I., Nagel, I."Genome‑wide expression and methylation analyses reveal aberrant cell adhesion signaling in tyrosine kinase inhibitor‑resistant CML cells". Oncology Reports 48, no. 2 (2022): 144. https://doi.org/10.3892/or.2022.8355