Department of Medical Biology, School of Medicine, Altinbas University, Istanbul, Turkey; Department of Medical Biology, School of Medicine, Ankara University, Ankara, Turkey.
Department of Medical Biology, School of Medicine, Usak University, Usak, Turkey.
Adv Med Sci. 2023 Sep;68(2):238-248. doi: 10.1016/j.advms.2023.06.002. Epub 2023 Jul 6.
Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of BCR-ABL protein. Imatinib (IMA) is considered as the first line therapy in management of CML which particularly targets the BCR-ABL tyrosine kinase protein. However, emergence of resistance to IMA hinders its clinical efficiency. Hence, identifying novel targets for therapeutic approaches in CML treatment is of great importance. Here, we characterize a new subpopulation of highly adherent IMA-resistant CML cells that express stemness and adhesion markers compared to naive counterparts.
We performed several experimental assays including FISH, flow cytometry, and gene expression assays. Additionally, bioinformatics analysis was performed by normalized web-available microarray data (GSE120932) to revalidate and introduce probable biomarkers. Protein-protein interactions (PPI) network was analyzed by the STRING database employing Cytoscape v3.8.2.
Our findings demonstrated that constant exposure to 5 μM IMA led to development of the adherent phenotype (K562R-adh). FISH and BCR-ABL expression analysis indicated that K562R-adh cells were derived from the original cells (K562R). In order to determine the role of various genes involved in epithelial-mesenchymal transition (EMT) and stem cell characterization, up/down-regulation of various genes including cancer stem cell (CSC), adhesion and cell surface markers and integrins were observed which was similar to the findings of the GSE120932 dataset.
Treating CML patients with tyrosine kinase inhibitors (TKIs) as well as targeting adhesion molecules deemed to be effective approaches in prevention of IMA resistance emergence which in turn may provide promising effects in the clinical management of CML patients.
慢性髓系白血病（CML）是一种血液系统恶性肿瘤，其特征是存在 BCR-ABL 蛋白。伊马替尼（IMA）被认为是 CML 管理的一线治疗方法，特别针对 BCR-ABL 酪氨酸激酶蛋白。然而，IMA 耐药的出现阻碍了其临床疗效。因此，确定 CML 治疗的新治疗靶点非常重要。在这里，我们描述了一种新的高度黏附性 IMA 耐药 CML 细胞亚群，与幼稚细胞相比，该亚群表达干性和黏附标志物。
我们进行了几项实验，包括 FISH、流式细胞术和基因表达分析。此外，通过正常化的可用微阵列数据（GSE120932）进行了生物信息学分析，以重新验证和引入可能的生物标志物。通过 STRING 数据库和 Cytoscape v3.8.2 分析蛋白质-蛋白质相互作用（PPI）网络。
我们的研究结果表明，持续暴露于 5 μM IMA 导致了黏附表型的发展（K562R-adh）。FISH 和 BCR-ABL 表达分析表明，K562R-adh 细胞来源于原始细胞（K562R）。为了确定涉及上皮-间充质转化（EMT）和干细胞特征的各种基因的作用，观察到各种基因的上调/下调，包括癌症干细胞（CSC）、黏附和细胞表面标志物以及整合素，这与 GSE120932 数据集的结果相似。
用酪氨酸激酶抑制剂（TKI）治疗 CML 患者以及靶向黏附分子被认为是预防 IMA 耐药性出现的有效方法，这可能会对 CML 患者的临床管理产生有希望的效果。
