Browsing by Author "Kiraz, Yağmur"

Now showing 1 - 2 of 2

Expression levels of JAK/STAT signaling genes in newly diagnosed, drug sensitive and resistant chronic myeloid leukemia patients
(Izmir Institute of Technology, 2014) Kiraz, Yağmur; Baran, Yusuf; Saydam, Güray
JAK/STAT signaling pathway has a role in transmission of information carried by cytokines, from outside of the cell to the nucleus. The system is run by the proteins known as Janus kinases (JAK) located on the cell membrane and STAT proteins acting as signal transducer and activator of transcription. JAK proteins activated by cytokines, phosphorylates and initiates the dimerization of STATs, which become active, move into nucleus and regulate expression of target genes. Previous studies demonstrated that there is overexpression of JAK/STAT genes in various types of cancer. The aim of this study is to examine the relationship between expression levels of JAK/STAT genes and clinical outcome of chronic myeloid leukemia (CML) patients. In this study expression levels of Jak/STAT pathway genes were analyzed in 23 different patients (1 patient responded positively, 1 only imatinib and 1 both imatinib and nilotinib resistant patients, 1 patient lost molecular response, 5 imatinib treated, and 14 newly diagnosed CML patients). The results showed that expression levels of Jak3, STAT1, STAT2, STAT3, STAT4 and STAT5A genes were overexpressed in TKI resistant patients. Expression levels of STAT5B, Jak1, Jak2 and Tyk2 genes were higher in newly diagnosed patients compared to resistant patients while STAT1 was lower in imatinib-treated patients. It was demonstrated for the first time that there is a relation between the clinical outcome of CML patients and expression levels of JAK-STAT genes that could make this signaling pathway a new target for more effective treatment of CML.
Sensitization of Philadelphia positive acute lymphoblastic leukemia cells resistant to imatinib by targeting sphingolipid metabolism
(Izmir Institute of Technology, 2019-11) Kiraz, Yağmur; Baran, Yusuf
Philadelphia positive acute lymphoblastic leukemia (Ph+ALL) is a common subtype of ALL and characterized by having BCR/ABL translocation. Tyrosine kinase inhibitors (TKI) such as imatinib are used for the treatment in Ph+ALL, however, 60-75% of the patients can develop resistance against the TKIs. Bioactive sphingolipids are a group of lipids that play roles in various cellular mechanisms. Previous studies showed that sphingolipids and genes in the pathway were involved in response to TKI treatment in Ph+ALL. Here, we investigated the roles of SPL on the growth inhibitory effects of imatinib and exploit sphingolipid metabolism by majorly inhibiting glucosylceramide synthase (GCS) to accumulate ceramide or sphingosine to further sensitize cells to imatinib and/or overcome resistance to imatinib in Ph+ALL. Firstly, we detected that, sphingosine kinase-1 (SK-1) a well-studied SPL enzyme inhibition did not contribute to cytotoxic effects of imatinib in SD-1 Ph+ALL cells. Moreover, we determined that imatinib is inducing de novo synthesis pathway of SPL and increasing the levels of ceramide, sphingosine, hexosylceramides and sphingomyelin in SD-1 cells. Interestingly, newly generated imatinib-resistant cell line SD-1R was detected to have an aberration in this pathway resulting in development of resistance. Combination treatment with eliglustat (GCS inhibitor) resulted in a significant increase in ceramide and sphingosine levels and reflected on cell growth and sensitized cells to imatinib. Taken together, it was shown for the first time in the literature that the cytotoxic effects of imatinib was due to induction of de novo synthesis pathway of sphingolipids and inhibition of GCS together with imatinib has synergistic cytotoxic effects on imatinib resistant Ph+ALL cells. As a conclusion, increasing the intracellular levels of ceramide (and/or sphingosine) can be a novel approach to sensitize drug resistant Ph+ALL cells.