title: Deregulated NOTCH signaling in acute T-cell lymphoblastic leukemia/lymphoma: new insights, questions, and opportunities.
abstract: Recent work has shown that the majority of human acute T-cell lymphoblastic leukemias and lymphomas (T-ALL) have gain-of-function mutations in NOTCH1, a type I transmembrane receptor that normally signals through a gamma-secretase-dependent mechanism that relies on ligand-induced regulated intramembranous proteolysis. Cleavage by gamma-secretase releases the intracellular domain of NOTCH1 (ICN1), permitting it to translocate to the nucleus and form a short-lived transcriptional activation complex that is essential for normal T-cell development. Two types of mutations are prevalent in human T-ALL: extracellular domain mutations that increase ICN1 production and C-terminal mutations that sustain ICN1 action. Inhibitors of ICN1 production and activity abrogate the growth of established T-ALL cell lines, and a clinical trial of a NOTCH pathway inhibitor in patients with refractory T-ALL has opened recently. These insights raise a number of new questions relevant to T-ALL pathogenesis and offer exciting opportunities for rational targeted therapy.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. jaster@rics.bwh.harvard.edu
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
mesh_terms: D019281:Dimerization; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000235:genetics*; D009154:Mutation; D051881:Receptor, Notch1 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology
chemical_list: D051881:Receptor, Notch1