Phenotypic and functional characterization of subpopulation of Imatinib resistant chronic myeloid leukemia cell line

Hekmatshoar, Yalda; Gurel, Aynur Karadag; Özkan, Tülin; Saadat, Yalda Rahbar; Koç, Aslı; Karabay, Arzu Zeynep; Bozkurt, Süreyya; Sunguroğlu, Asuman

doi:10.1016/j.advms.2023.06.002

Advances in Medical Sciences

2023

DOI: 10.1016/j.advms.2023.06.002

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Phenotypic and functional characterization of subpopulation of Imatinib resistant chronic myeloid leukemia cell line

Yalda Hekmatshoar

Aynur Karadag Gurel

Tülin Özkan

et al.

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2024

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Cited by 2 publications

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Identification of exosomal microRNAs and related hub genes associated with imatinib resistance in chronic myeloid leukemia

Karabay,

Ozkan,

Karadag Gurel

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Chemotherapy resistance is a major obstacle in cancer therapy, and identifying novel druggable targets to reverse this phenomenon is essential. The exosome-mediated transmittance of drug resistance has been shown in various cancer models including ovarian and prostate cancer models. In this study, we aimed to investigate the role of exosomal miRNA transfer in chronic myeloid leukemia drug resistance. For this purpose, firstly exosomes were isolated from imatinib sensitive (K562S) and resistant (K562R) chronic myeloid leukemia (CML) cells and named as Sexo and Rexo, respectively. Then, miRNA microarray was used to compare miRNA profiles of K562S, K562R, Sexo, Rexo, and Rexo-treated K562S cells. According to our results, miR-125b-5p and miR-99a-5p exhibited increased expression in resistant cells, their exosomes, and Rexo-treated sensitive cells compared to their sensitive counterparts. On the other hand, miR-210-3p and miR-193b-3p were determined to be the two miRNAs which exhibited decreased expression profile in resistant cells and their exosomes compared to their sensitive counterparts. Gene targets, signaling pathways, and enrichment analysis were performed for these miRNAs by TargetScan, KEGG, and DAVID. Potential interactions between gene candidates at the protein level were analyzed via STRING and Cytoscape software. Our findings revealed CCR5, GRK2, EDN1, ARRB1, P2RY2, LAMC2, PAK3, PAK4, and GIT2 as novel gene targets that may play roles in exosomal imatinib resistance transfer as well as mTOR, STAT3, MCL1, LAMC1, and KRAS which are already linked to imatinib resistance. MDR1 mRNA exhibited higher expression in Rexo compared to Sexo as well as in K562S cells treated with Rexo compared to K562S cells which may suggest exosomal transfer of MDR1 mRNA. Graphical Abstract

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Identification of exosomal microRNAs and related hub genes associated with imatinib resistance in chronic myeloid leukemia

Karabay,

Ozkan,

Karadag Gurel

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Global DNA Methylation analysis of imatinib resistant and sensitive K562 cells

Hekmatshoar

2024

Ege Tıp Bilimleri Dergisi

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OBJECTIVE: Chronic myeloid leukemia (CML) is a hematological disease which is known by the presence of Philadelphia chromosome (Ph+). BCR-ABL protein is expressed by Ph+ chromosome, represents constant increased tyrosine kinase activity. Imatinib (IMA) is a tyrosine kinase inhibitor (TKI) which is utilized as a first line treatment in CML. Emergence of IMA resistance at some point of therapy leads to treatment failure. DNA methylation is considered to be the most stable epigenetic change and several studies have shown that epigenetic changes may play a role in drug resistance. We investigated the global methylation profile of IMA-sensitive K562S, IMA-resistant K562R and IMA-resistant and adherent K562R (K562R-adh) cells to determine whether epigenetic reprogramming is involved in the resistance to IMA and the change in phenotype due to this resistance. MATERIAL AND METHODS: In this study, morphologically distinct, IMA-sensitive K562S and 5µM IMA-resistant K562R and K562R-adh in-vitro CML cell models were used to analyze the global DNA methylation profile. After DNA was isolated from the cells, global 5mC DNA methylation profiles were investigated by ELISA using equal amounts of DNA. RESULTS: Compared to K562S, the global methylation of K562R showed an increase in DNA methylation profile, but this increase in methylation was not statistically significant. Whereas, a slight hypermethylation was observed in the DNA of the K562R-adh vs K562S and K562R-adh vs K562R which is statistically significant. We observed slight hypermethylation in IMA-resistant cells lines versus to the IMA-sensitive cell line. CONCLUSION: Our observed differences in 5methyl-Cytosine on CpG islands (5mC) in K562S versus K562R and K562R-adh cell lines suggest that the DNA methylation alteration in resistant cells may partly contributed in phenotype switching.

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Phenotypic and functional characterization of subpopulation of Imatinib resistant chronic myeloid leukemia cell line

Cited by 2 publications

References 45 publications

Identification of exosomal microRNAs and related hub genes associated with imatinib resistance in chronic myeloid leukemia

Identification of exosomal microRNAs and related hub genes associated with imatinib resistance in chronic myeloid leukemia

Global DNA Methylation analysis of imatinib resistant and sensitive K562 cells

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