关键词： 5-aminoimidazole-4-carboxamide ribonucleotide ADAM AICAR AKT ALL AML AMPK ANK B-cell chronic lymphocytic leukemia B-precursor acute lymphoblastic leukemia BAD BCL-2 associated death promoter BCL-2 homology domain 3 (BH3)-only protein, B-cell lymphoma 2 interacting mediator of cell death BP-ALL Bim CAMKKβ CBF1/Su(H)/Lag-1 CDK8 CK2 CLL CSL DSL Delta-like Delta–Serrate–Lag1 Dll EFS EGF ERK F-box/WD-repeat containing protein 7 FBW7 FOXO GSC GSI GSK3 HD Hes1 ICN1 IGF1R IGFBP3 IL7Rα IRS1 JME Jag Jagged LKB1 LNR Leukemia Lin12/Notch1 repeats MAML1 MAPK MCL1 MDM2 NEC NTM Notch1 Notch1 extracellular domain Notch1 transmembrane domain PDK1 PEST PI3K PIP(2) PIP(3) PKCθ PP2A PRAS40 PTEN Pro, Glu, Ser, and Thr-rich domain Protein phosphatase 2A ROS RUNX1 and RUNX3 Ser/Thr-protein phosphatase 2A T-ALL T-cell acute lymphoblastic leukemia TACE TAN1 a disintegrin and metalloprotease acute lymphoblastic leukemia acute myeloid leukemia adenosine monophosphate (AMP) activated protein kinase ankyrin-like repeats calmodulin-dependent protein kinase kinase beta casein kinase 2 cyclin-dependent kinase 8 eIF2A and eIF4E epidermal growth factor eukaryotic translation initiating factors 2A and 4E event free survival extracellular signal-regulated protein kinase fork head box O transcription factors glycogen synthase kinase 3 hairy and enhancer of split-1 heterodimerization domain induced myeloid leukemia cell differentiation protein insulin receptor substrate 1 insulin-like growth factor 1 receptor insulin-like growth factor-binding protein 3 interleukin-7 receptor subunit α intracellular domain of Notch1 juxtamembrane expansion liver kinase B1 mSIN1 mTOR mammalian stress-activated protein kinase interacting protein 1 mammalian target of rapamycin mastermind-like protein 1 miR/miRNA micro-RNA mitogen activate protein kinases mouse double minute 2 homolog phosphatase and tensin homolog deleted on chromosome ten phosphatidylinositide 3-kinase phosphatidylinositol (3,4,5)-trisphosphate phosphatidylinositol (4,5)-bisphosphate phosphoinositide dependent protein kinase-1 proline-rich AKT substrate 40kDa protein kinase B (PKB) protein kinase C theta rapamycin-insensitive companion of mTOR raptor reactive oxygen species regulatory-associated protein of mTOR rictor runt-related transcription factors 1 and 3 translocation associated Notch1 homolog tumor necrosis factor α-converting enzyme γ-Secretase inhibitor resistance γ-secretase complex γ-secretase complex inhibitors

Mesh ： Amyloid Precursor Protein Secretases / antagonists & inhibitors metabolism Animals Drug Resistance, Neoplasm / drug effects Enzyme Inhibitors / pharmacology therapeutic use Humans Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy enzymology pathology Receptors, Notch / metabolism Signal Transduction / drug effects

来  源：   DOI：10.1016/j.cellsig.2013.09.021   PDF(Sci-hub)

Abstract：
T-cell acute lymphoblastic leukemia (T-ALL) is characterized as a high-risk stratified disease associated with frequent relapse, chemotherapy resistance, and a poorer prognostic outlook than B-precursor ALL. Many of the challenges in treating T-ALL reflect the lack of prognostic cytogenetic or molecular abnormalities on which to base therapy, including targeted therapy. Notch1 activating mutations were identified in more than 50% of T-ALL cases and can be therapeutically targeted with γ-secretase inhibitors (GSIs). Mutant Notch1 can activate cMyc and PI3K-AKT-mTOR1 signaling in T-ALL. In T-ALLs with wild-type phosphatase and tensin homolog deleted on chromosome ten (PTEN), Notch1 transcriptionally represses PTEN, an effect reversible by GSIs. Notch1 also promotes growth factor receptor (IGF1R and IL7Rα) signaling to PI3K-AKT. Loss of PTEN is common in primary T-ALLs due to mutation or posttranslational inactivation and results in chronic activation of PI3K-AKT-mTOR1 signaling, GSI-resistance, and repression of p53-mediated apoptosis. Notch1 itself might regulate posttranslational inactivation of PTEN. PP2A is activated by Notch1 in PTEN-null T-ALL cells, and GSIs reduce PP2A activity and increase phosphorylation of AKT, AMPK, and p70S6K. This review focuses on the central role of the PI3K-AKT-mTOR1 signaling in T-ALL, including its regulation by Notch1 and potential therapeutic interventions, with emphasis on GSI-resistant T-ALL.
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