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  • Küçük Resim
    Öğe
    Characterization of imatinib-resistant K562 cell line displaying resistance mechanisms
    (C M B Assoc, 2018) Hekmatshoar, Yalda; Özkan, Tülin; Güneş, Buket Altınok; Bozkurt, Süreyya; Karadağ, Aynur; Karabay, Arzu Zeynep; Sunguroğlu, Asuman
    Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by the t(9; 22) and the related oncogene, BCR-ABL. Tyrosine kinase activity of fusion protein BCR-ABL is the main cause of CML. Even if imatinib is used as a tyrosine kinase inhibitor (TKI) for CML therapy. drug resistance may occur in patients and the clinical failure of imatinib treatment in resistant patients had resulted with the use of another alternative TKIs. BCR-ABL dependent and independent molecular mechanisms have crucial roles in drug resistance. To reveal the underlying molecular mechanisms which play significant roles in imatinib resistance in CML, we established K562 imatinib-resistant cell line (K562r5) which was continuously exposed to (5 mu M) imatinib to investigate molecular mechanisms which play significant roles in drug resistance. First of all, we analyzed T315I. M351T, F315L and F359C/L/V mutations with DNA sequencing as a BCR-ABL dependent mechanism in our cell lines. Moreover, we investigated BCR-ABL independent mechanisms such as apoptosis. autophagy, drug transport and DNA repair which affect drug resistance in these cell lines. In vitro cell viability was determined by MTT assay. DNA sequencing analysis was performed to detect BCR-ABL mutations. The apoptotic effect of imatinib on CML cell lines was tested by flow cytometric Annexin V-PE staining and caspase activation assays. Apoptotic, autophagic, drug transporter and DNA repair genes expression levels were determined by RT-PCR. The conventional cytogenetic analysis was performed on K562s and K562r cells. Our results indicate that inhibition of apoptosis, induction of autophagy, overexpression of efflux gene MDR1 and down-regulation of influx gene OCT1 play crucial roles in the progression of imatinib resistance.
  • Küçük Resim
    Öğe
    Downregulation of stearoyl-CoA desaturase 1 (SCD-1) promotes resistance to imatinib in chronic myeloid leukemia
    (Mattioli 1885, 2022) Günes, Buket Altınok; Hekmatshoar, Yalda; Özkan, Tülin; Bozkurt, Süreyya; Aydos, Oya Sena Erdoğan; Büyükaşık, Yahya; Aladağ, Elifcan; Asuman Sunguroğlu
    Chronic myeloid leukemia (CML) is a malignant hematopoietic stem cell disease resulting in the fusion of BCR and ABL genes and characterized by the presence of the reciprocal translocation t(9;22)(q34;q11). BCR-ABL, a product of the BCR-ABL fusion gene, is a structurally active tyrosine kinase and plays an important role in CML disease pathogenesis. Imatinib mesylate (IMA) is a strong and selective BCR-ABL tyrosine kinase inhibitor. Although IMA therapy is an effective treatment, patients may develop resistance to IMA therapy over time. This study investigated the possible genetic resistance mechanisms in patients developing resistance to IMA. We did DNA sequencing in order to detect BCR-ABL mutations, which are responsible for IMA resistance. Moreover, we analyzed the mRNA expression levels of genes responsible for apoptosis, such as BCL-2, P53, and other genes (SCD-1, PTEN). In a group of CML patients resistant to IMA, when compared with IMA-sensitive CML patients, a decrease in SCD-1 gene expression levels and an increase in BCL-2 gene expression levels was observed. In this case, the SCD-1 gene was thought to act as a tumor suppressor. The present study aimed to investigate the mechanisms involved in IMA resistance in CML patients and determine new targets that can be beneficial in choosing the effective treatment. Finally, the study suggests that the SCD-1 and BCL-2 genes may be mechanisms responsible for resistance.