Deregulated NOTCH signaling in acute T-cell lymphoblastic leukemia/lymphoma: New insights, questions, and opportunities

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 ill 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.