ABSTRACT
Thomas Hunt Morgan first described a mutant Drosophila melanogaster strain with “notched” wings in 1917. Notch signaling is critical for several cell fate determinations in mammalian organisms including the T- versus B-lineage choice in early hematopoietic progenitors. Notch signaling promotes the proliferation, differentiation, and survival of early T-cell progenitors. The multicomponent γ-secretase enzyme complex that cleaves Notch to release the Notch intracellular domain also cleaves the amyloid precursor protein, leading to the production of plaques in Alzheimer’s patients. Although several human T-ALL cell lines are sensitive to γ-secretase inhibitor treatment, most lines are resistant to the drug and proliferate normally despite evidence of Notch pathway activation. Inhibition of the Notch signaling pathway has opened up a new area for therapeutic intervention. The complexity of the Notch signaling pathway provides several additional points at which the pathway could be targeted including ligand binding, dimerization, proteolysis, and transcriptional activity.
