title: New insights into Notch1 regulation of the PI3K-AKT-mTOR1 signaling axis: targeted therapy of γ-secretase inhibitor resistant T-cell acute lymphoblastic leukemia.
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.
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Hales
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Taub
authors.forename: Larry H
authors.initials: LH
authors.lastname: Matherly
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases
keywords: 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