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• W2465087626 abstract "T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of pediatric and 25% of adult ALL. With cure rates of ~80% in children and ~40% in adults, there is an urgent need to identify and understand the signaling pathways in T-ALL in order to develop the first targeted therapies for this cancer. The most prevalent oncogene is NOTCH1, which is mutated in about 60% of patient samples [1]. Normally, Notch is restrained by the heterodimerization domain (HD, Figure 1). Notch becomes activated once it engages ligand. γ-secretase cleaves Notch, thus releasing the intracellular domain of Notch (ICN). ICN binds Rbpj and Maml to activate transcription. ICN has a short half-life as phosphodegron motifs in its PEST domain are recognized by the ubiquitin ligase Fbxw7, which targets it for destruction [2,3]. PEST domain deletions improve ICN stability [4]. Mutations in the HD domain trigger ligand-independent activation [5,6]. Target genes of NOTCH1 that drive leukemia include MYC [7–9], HES1 [10], IGF-1R [11], TRIB2 [12], and IL7R [13]. Notch also activates the PI3K/Akt/mTor pathway [11,14,15].Figure 1Model of oncogenic NOTCH1 signaling in T-ALL. NOTCH1 is normally locked in an “off” state, which blocks S2 cleavage. Mutations that discrupt the integrity of the heterodimerization domain (HD, e.g. L1601P) permit ligand-independent S2 ...Collaborative pathways confer resistance to NOTCH inhibitorsγ-secretase inhibitors (GSIs) block Notch signaling (Figure 1). GSIs are being tested in clinical trials in T-ALL and other NOTCH-driven cancers [16–18]. Initial reports show promising activity. However, resistance is an emerging problem. Approximately two-thirds of human T-ALL cell lines are resistant to GSI [1]. GSI depletes ICN in resistant cells just as it does in sensitive cells [7,15]. Thus, cancers resist GSI by activating collaborating pathways to bypass the effects of NOTCH1 inhibition. We previously showed that NOTCH1 mutations are moderate oncogenes in mouse models [19]. Collaborating oncogenic networks are essential to functionally enhance NOTCH1 signaling to leukemogenic levels. These findings have shifted the field toward identifying pathways that collaborate with the NOTCH pathway." @default.
• W2465087626 created "2016-07-22" @default.
• W2465087626 creator A5039019694 @default.
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• W2465087626 date "2013-01-01" @default.
• W2465087626 modified "2023-09-23" @default.
• W2465087626 title "Collaborating Pathways that Functionally Amplify NOTCH1 Signals in T-Cell Acute Lymphoblastic Leukemia." @default.
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• W2465087626 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4798248" @default.
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