WoS İndeksli Yayınlar Koleksiyonu

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/394

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  • Article
    Citation - WoS: 29
    Citation - Scopus: 30
    Revealing Genome-Wide mRNA and MicroRNA Expression Patterns in Leukemic Cells Highlighted HSA-MIR as a Tumor Suppressor for Regain of Chemotherapeutic Imatinib Response due to Targeting STAT5A
    (Sage Publications Ltd, 2015-05-08) Kaymaz, Burcin Tezcanli; Gunel, Nur Selvi; Ceyhan, Metin; Cetintas, Vildan Bozok; Ozel, Buket; Yandim, Melis Kartal; Can, Buket Kosova
    BCR-ABL oncoprotein stimulates cell proliferation and inhibits apoptosis in chronic myeloid leukemia (CML). For cure, imatinib is a widely used tyrosine kinase inhibitor, but developing chemotherapeutic resistance has to be overcome. In this study, we aimed to determine differing genome-wide MicroRNA (miRNA) and messenger RNA (mRNA) expression profiles in imatinib resistant (K562/IMA-3 mu M) and parental cells by targeting STAT5A via small interfering RNA (siRNA) applications. After determining possible therapeutic miRNAs, we aimed to check their effects upon cell viability and proliferation, apoptosis, and find a possible miRNA
  • Article
    Citation - WoS: 1
    Citation - Scopus: 1
    Concurrent Inhibition of FLT3 and Sphingosine Kinase-1 Triggers Synergistic Cytotoxicity in Midostaurin Resistant FLT3-ITD Positive Acute Myeloid Leukemia Cells via Blocking FLT3/TAT5A Signaling to Induce Apoptosis
    (Taylor & Francis Ltd, 2025-03-21) Tecik, Melisa; Adan, Aysun
    The FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations observed in acute myeloid leukemia (AML) which contributes to disease progression and unfavorable prognosis. Midostaurin, a small FLT3 inhibitor (FLT3I), is clinically approved. However, patients generally possess acquired resistance when midostaurin used alone. Shifting the balance in the sphingolipid rheostat toward anti-apoptotic sphingosine kinase-1 (SK-1) or glucosylceramide synthase (GCS) is related to therapy resistance in cancer, however, their role in midostaurin resistant FLT3-ITD positive AML has not been previously investigated. We generated midostaurin resistant MV4-11 and MOLM-13 cell lines which showed increased IC50 values compared to their sensitive partner cells. SK-1 is overexpressed in resistant cells while GCS remains unchanged. Subsequent pharmacological targeting of SK-1 in resistant cells decreased SK-1 protein level, inhibited cell proliferation and showed additive or synergistic effect on cell growth, as confirmed by the Chou-Talalay combination index, and induced G0/G1 arrest (PI staining by flow cytometry). Cotreatment (SKI-II plus midostaurin) triggered apoptosis via phosphatidylserine exposure (annexin V/PI double staining). Mechanistically, induction of the intrinsic pathway of apoptosis was confirmed as increased activating cleavages of caspase-3 and PARP and increased Bax/Bcl-2 ratios. Activating phosphorylations of FLT3 (at tyrosine residue 591) and STAT5A (at tyrosine residue 694) dramatically inhibited in resistant cells treated with the combination. In conclusion, midostaurin resistance could be reversed by dual SK-1 and FLT3 inhibition in midostaurin resistant AML cell lines, providing the first evidence of a novel treatment approach to re-sensitize FLT3-ITD positive AML.