The identification of activating mutations in NOTCH1 in over 50% of T-cell acute 
lymphoblastic leukemias (T-ALL) has generated major interest in the elucidation 
of the mechanisms of transformation downstream of oncogenic NOTCH and in the 
targeting of the NOTCH signaling pathway in this disease. Small molecule 
gamma-secretase inhibitors (GSIs) block NOTCH1 signaling in T-ALL lymphoblasts, 
yet the clinical development of GSIs has been held back by the development of 
gastrointestinal toxicity and their weak antileukemic effects against human 
T-ALL. However, new therapeutic strategies aiming to optimize the use of 
anti-NOTCH1 therapies for T-ALL, including combination therapies with 
molecularly targeted drugs and glucocorticoids, have started to emerge as a 
result of improved understanding of the molecular mechanisms that mediate the 
effects of GSIs in leukemic cells and the intestinal epithelium. This review 
focuses on the molecular basis of NOTCH1-induced transformation, the mechanisms 
of action of oncogenic NOTCH1 and clinical significance of NOTCH1 mutations in 
T-ALL.