Deregulated NOTCH Signaling in Acute T-Cell Lymphoblastic Leukemia/Lymphoma: New Insights, Questions, and Opportunities
- Cite this article as:
- Aster, J.C. Int J Hematol (2005) 82: 295. doi:10.1532/IJH97.05096
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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 7-secretase-dependent mechanism that relies on ligand-induced regulated intramembranous proteolysis. Cleavage by 7-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.