Therapeutic targeting of NOTCH1 signaling in T-cell acute lymphoblastic leukemia.
The recent identification of activating mutations in NOTCH1 in the majority of T-cell acute lymphoblastic leukemias (T-ALLs) has brought major interest toward targeting the NOTCH signaling pathway in this disease. Small-molecule gamma-secretase inhibitors (GSIs), which block a critical proteolytic step required for NOTCH1 activation, can effectively block the activity of NOTCH1 mutant alleles. However, the clinical development of GSIs has been hampered by their low cytotoxicity against human T-ALL and the development of significant gastrointestinal toxicity derived from the inhibition of NOTCH signaling in the gut. Improved understanding of the oncogenic mechanisms of NOTCH1 and the effects of NOTCH inhibition in leukemic cells and the intestinal epithelium are required for the design of effective anti-NOTCH1 therapies in T-ALL.
Palomero
Teresa
T
Department of Pathology, Institute for Cancer Genetics, Columbia University, New York, USA.
Ferrando
Adolfo
A
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D008024:Ligands; C497761:NOTCH1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases; D053829:Amyloid Precursor Protein Secretases