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.