Please use this identifier to cite or link to this item: https://hdl.handle.net/11147/10912
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dc.contributor.advisorBaran, Yusuf-
dc.contributor.authorKiraz, Yağmur-
dc.date.accessioned2020-12-01T11:21:59Z-
dc.date.accessioned2021-07-02T08:48:42Z-
dc.date.available2020-12-01T11:21:59Z-
dc.date.available2021-07-02T08:48:42Z-
dc.date.issued2019-11en_US
dc.identifier.citationKiraz, Y. (2019). Sensitization of Philadelphia positive acute lymphoblastic leukemia cells resistant to imatinib by targeting sphingolipid metabolism. Unpublished doctoral dissertation, İzmir Institute of Technology, İzmir, Turkeyen_US
dc.identifier.urihttps://hdl.handle.net/11147/10912-
dc.descriptionThesis (Doctoral)--Izmir Institute of Technology, Molecular Biology and Genetics, Izmir, 2019en_US
dc.descriptionIncludes bibliographical references (leaves: 98-123)en_US
dc.descriptionText in English; Abstract: Turkish and Englishen_US
dc.description.abstractPhiladelphia 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.en_US
dc.description.abstractPhiladelphia pozitif akut lenfoblastik lösemi (Ph+ALL), ALL'nin sıklıkla görülen bir alt tipi olmakla birlikte, BCR/ABL translokasyonunu taşımakla karakterizedir. Ph+ ALL tedavisinde, imatinib gibi tirozin kiraz inhibitörleri (TKİ) kullanılmasına rağmen, hastaların %60-75'i TKİ'lere karşı direnç geliştirmektedir. Biyoaktif sfingolipidler, birçok hücresel mekanizmada rol oynayan bir lipid grubudur. Daha önce yapılan çalışmalar biyoaktif sfingolipidlerin ve bu yolaktaki genlerin Ph+ALL'de TKİ'ye verilen yanıtta rol aldığını göstermiştir. Bu çalışmada, biyoaktif sfingolipidlerin imatinibin büyümeyi baskılayıcı rollerini ve sfingolipid metabolizmasından özellikle glukozilseramid sentaz (GSS) ve sfingozin kinaz-1'i (SK-1) inhibe ederek seramid veya sfingozinin birikimine yol açarak hücreleri imatinibe duyarlı hale getirmeyi ve/veya direnci geri çevirmeyi araştırdık. Öncelikle, daha önce çalışılmış bir sfingolipid enzimi olan SK-1 inhibisyonunun imatinibin SD-1 Ph+ALL hücreleri üzerine sitotoksik etkilerine katkı yapmadığını tespit ettik. Daha da önemlisi, imatinibin sfingolipidlerin de novo sentez yolağını tetiklediğini ve seramid, sfingozin, heksozilseramid ve sfingomyelin düzeylerini artırdığını belirledik. İlginç bir şekilde, yeni geliştirilen imatinib-dirençli SD-1R hücrelerinde bu yolakta tespit edilen bir anormallik direnç gelişimine neden olmuştur. Eliglustat (GSS inhibitörü) ile imatinibin kombinasyon tedavisi, seramid ve sfingozin seviyelerinde önemli artışa neden olarak, hücreleri imatinibe duyarlı hale getirdi. Tüm bu veriler değerlendirildiğinde, imatinibin sitotoksik etkilerinin de novo sentez yolağının aktifleştirilmesi ile olduğu ve GSS inhibisyonu ile imatinib uygulamasının imatinib-dirençli Ph+ALL hücrelerinde sinerjik sitotoksik etkileri olduğu literatürde ilk defa bu çalışma ile gösterilmiştir. Sonuç olarak, hücre içi seramid (ve/veya sfingozin) düzeylerinin artırılması, ilaç dirençli Ph+ALL hücrelerinin duyarlı hale getirilmesi için yeni bir yaklaşım olabilir.en_US
dc.format.extentxiv, 123 leavesen_US
dc.language.isoenen_US
dc.publisherIzmir Institute of Technologyen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectLymphoblastic leukemiaen_US
dc.subjectAcute lymphoblastic leukemiaen_US
dc.subjectPh+ALL cellsen_US
dc.subjectCanceren_US
dc.subjectCancer cellsen_US
dc.subjectSphingolipidsen_US
dc.titleSensitization of Philadelphia positive acute lymphoblastic leukemia cells resistant to imatinib by targeting sphingolipid metabolismen_US
dc.title.alternativeSfingolipid metabolizmasının hedeflenmesiyle imatinibe dirençli Philadelphia pozitif akut lenfoblastik lösemi hücrelerinin duyarlı hale getirilmesien_US
dc.typeDoctoral Thesisen_US
dc.departmentIzmir Institute of Technology. Molecular Biology and Geneticsen_US
dc.relation.publicationcategoryTezen_US
item.openairetypeDoctoral Thesis-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.languageiso639-1en-
item.fulltextWith Fulltext-
item.grantfulltextopen-
item.cerifentitytypePublications-
crisitem.author.dept04.03. Department of Molecular Biology and Genetics-
Appears in Collections:Phd Degree / Doktora
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