The role of NOTCH1 signaling in T-ALL

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 down-stream of oncogenic NOTCH and in the targeting of the NOTCH signaling pathway in this disease. Small molecule γ-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. T-cell acute lymphoblastic leukemia (T-ALL) ischaracterized by infiltration of the bone marrow withimmature lymphoblasts expressing T-cell immunophenotypic markers. T-ALL accounts for 10 % to 15 % of pediatric and 25 % of adult acute lymphoblastic leukemia cases. T-ALL patients frequently show a larg