Please use this identifier to cite or link to this item: https://scholarbank.nus.edu.sg/handle/10635/218206
Title: IDENTIFICATION OF A THERAPEUTIC COMPOUND TARGETING THE CORE ONCOGENIC MACHINERY IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: LIM FANG QI
Keywords: T-cell acute lymphoblastic leukemia, transcription factor, kinase inhibitor, small molecule inhibitor
Issue Date: 1-Oct-2021
Citation: LIM FANG QI (2021-10-01). IDENTIFICATION OF A THERAPEUTIC COMPOUND TARGETING THE CORE ONCOGENIC MACHINERY IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA. ScholarBank@NUS Repository.
Abstract: T-ALL is a malignancy of thymic T-cell precursors. Overexpression of oncogenic transcription factor TAL1 is observed in 40-60% of human T-ALL cases, frequently together with activation of the NOTCH1 and PI3K-AKT pathways. Small molecule screening identified PIK-75, a known inhibitor of PI3K and CDKs, was found to strongly inhibit GIMAP enhancer activity. Mechanistic analysis demonstrated that PIK-75 blocks transcriptional activity, which primarily affects TAL1 target genes as well as AKT activity. Notably, TAL1-positive, AKT-activated T-ALL cell lines were very sensitive to PIK-75, as evidenced by the strong growth inhibition and apoptosis induction observed, while cell lines that exhibited activation of the JAK-STAT pathway were relatively resistant to this drug. The cell growth inhibitory effect was also confirmed in patient-derived human T-ALL cells. Taken together, our results demonstrated that PIK-75 can exert potent cytotoxicity through inhibition of core oncogenic machineries mediated by TAL1 and PI3K-AKT in T-ALL.
URI: https://scholarbank.nus.edu.sg/handle/10635/218206
Appears in Collections:Ph.D Theses (Restricted)

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