The role of NOTCH1 signaling in T-ALL

AA Ferrando - ASH Education Program Book, 2009 - ashpublications.org
AA Ferrando
ASH Education Program Book, 2009ashpublications.org
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 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 …
Abstract
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 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.
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