Gamma Secretase Inhibitor: Therapeutic Target via NOTCH Signaling in T Cell Acute Lymphoblastic Leukemia

Background: T-cell acute lymphoblastic leukemia (T-ALL) is a diseased condition of bone marrow and lymphoblast, mainly expressed on T-cell immune phenotype Diagnosis of TALL patients shows the burden of a large tumour and leukemia cells in the peripheral blood vessel which often infiltrates into the central nervous system. Objective: Chemotherapy is considered the primary mode of treatment for this disease, but recent advancements in the molecular understanding of the disease, including NOTCH1 signaling, could offer some alternatives. NOTCH signaling undergoes a non-regulated mutation at NOTCH1 in most T-ALL. Gamma-secretase (GS) plays a key role in blocking of proteolytic activation of NOTCH receptors, which could potentially be a new targeted therapy for this type of leukaemia. This study mainly aims to outline the role of gamma-secretase inhibitors via NOTCH signaling in T-ALL. Results: The role of GSI (gamma-secretase inhibitor) in most T-ALL cell lines has been linked to the targeting pathway of NOTCH signaling. Mutation at NOTCH1 has however not served as a predictor of gamma-secretase inhibitor sensitivity because of several factors, including gene expression of NOTCH pathway activity. Therefore, despite the promising outcome of this approach in NOTCH-1 activated T-ALL, not all patients with this condition are expected to respond. Conclusion: Long-term therapeutic success against cancerous cells is rarely achieved with monotherapy, and even targeting investigational pathways such as NOTCH may require a combination regimen. Ultimately, the optimised use of these new therapeutic agents may become the next tool in our search for an effective 'individualized medicine'.

Automated summary

T-cell acute lymphoblastic leukemia (T-ALL) is mainly treated with chemotherapy, but recent studies on the NOTCH signaling pathway suggest potential new targeted therapies. While gamma-secretase inhibitors have shown promising results in targeting NOTCH signaling in T-ALL cell lines, mutations in NOTCH1 do not always predict sensitivity to these inhibitors. Therefore, a combination regimen may be necessary for effective long-term treatment against T-ALL.