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dc.contributor.authorKaehler, Meike
dc.contributor.authorLitterst, Merit
dc.contributor.authorKolarova, Julia
dc.contributor.authorBohm, Ruwen
dc.contributor.authorBruckmueller, Henrike
dc.contributor.authorAmmerpohl, Ole
dc.contributor.authorCascorbi, Ingolf
dc.contributor.authorNagel, Inga
dc.date.accessioned2022-11-30T15:04:33Z
dc.date.available2022-11-30T15:04:33Z
dc.date.issued2022-06-22
dc.description.abstractAlthough 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.en_US
dc.identifier.citationKaehler, Litterst, Kolarova, Bohm, Bruckmueller, Ammerpohl, Cascorbi, Nagel. Genome-wide expression and methylation analyses reveal aberrant cell adhesion signaling in tyrosine kinase inhibitor-resistant CML cells. Oncology Reports. 2022;48(2)en_US
dc.identifier.cristinIDFRIDAID 2053328
dc.identifier.doi10.3892/or.2022.8355
dc.identifier.issn1021-335X
dc.identifier.issn1791-2431
dc.identifier.urihttps://hdl.handle.net/10037/27626
dc.language.isoengen_US
dc.publisherSpandidos Publicationsen_US
dc.relation.journalOncology Reports
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2022 The Author(s)en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0en_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)en_US
dc.titleGenome-wide expression and methylation analyses reveal aberrant cell adhesion signaling in tyrosine kinase inhibitor-resistant CML cellsen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
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