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 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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Review
MeSH terms
-
Amyloid Precursor Protein Secretases / antagonists & inhibitors
-
Amyloid Precursor Protein Secretases / physiology
-
Animals
-
Antineoplastic Combined Chemotherapy Protocols / adverse effects
-
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
-
Cell Transformation, Neoplastic / genetics
-
Clinical Trials, Phase I as Topic
-
Cocarcinogenesis
-
Early Termination of Clinical Trials
-
Gene Expression Regulation, Leukemic / genetics
-
Gene Expression Regulation, Leukemic / physiology*
-
Glucocorticoids / administration & dosage
-
Humans
-
Lymphopoiesis / genetics
-
Lymphopoiesis / physiology
-
Mice
-
Mice, Transgenic
-
Mutation
-
Neoplasm Proteins / antagonists & inhibitors
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / physiology*
-
Oncogene Proteins, Fusion / genetics
-
Oncogene Proteins, Fusion / physiology
-
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / embryology
-
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
-
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / physiopathology*
-
Preleukemia / genetics
-
Prognosis
-
Receptor, Notch1 / antagonists & inhibitors
-
Receptor, Notch1 / genetics
-
Receptor, Notch1 / physiology*
-
Signal Transduction / genetics
-
Signal Transduction / physiology*
-
Translocation, Genetic
Substances
-
Glucocorticoids
-
NOTCH1 protein, human
-
Neoplasm Proteins
-
Oncogene Proteins, Fusion
-
Receptor, Notch1
-
Amyloid Precursor Protein Secretases