Activating NOTCH1 mutations increase T-ALL cells' chemosensitivity by altering PREX2-AKT pathway

Mutations on NOTCH1 gene are the most commonly found mutations in T-cell acute lymphoblastic leukemia (T-ALL) and they are reported to be favorable indicators for T-ALL patients' prognosis. However, the effects of activating NOTCH1 mutations on T-ALL's chemosensitivity have not been studied. We reported that NOTCH1 inhibition by gamma-secretase inhibitors or shRNA knockdown in MOLT-3 cells could reduce the T-ALL cells' sensitivity to chemotherapeutic drugs. However, this effect was absent in Jurkat and CUTLL1 cells. We further demonstrated that NOTCH1 inhibition could activate the PI3K-AKT pathway in a cell specific pattern similar as their effects on chemosensitivity. RNA-seq revealed that Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 2 (PREX2) is a target gene of NOTCH1 and may mediate the effects of activating NOTCH1 mutations on chemosensitivity. Consistently, we proved that overexpression of PREX2 could mimic the effects of NOTCH1 inhibition on chemosensitivity. Our study has highlighted the effects of activating NOTCH1 mutations on T-ALL's chemosensitivity by altering PREX2-AKT pathway, which may explain the favorable effects of NOTCH1 mutations on T-ALL patients' prognosis, as well as provided potential targets to sensitize T-ALL cells to chemotherapy. Overall design: To search for NOTCH1 regulated genes which may contribute to the effects of NOTCH1 on T-ALL cells' chemosensitivity, the transcriptomes of compound E and DMSO treated MOLT-3 cells were analyzed by RNA-seq.