Abstract
The Notch signaling pathway is highly conserved from Drosophila to humans and plays an important role in the regulation of cellular proliferation, differentiation and apoptosis.Constitutive activation of Notch signaling has been shown to result in excessive cellular proliferation and a wide range of malignancies, including leukemia, glioblastoma and lung and breast cancers. Notch can also act as a tumor suppressor, and its inactivation has been associated with an increased risk of spontaneous squamous cell carcinoma. This minireview focuses on recent advances related to the mechanisms and roles of activated Notch1, Notch2, Notch3 and Notch4 signaling in human lymphocytic leukemia, myeloid leukemia and B cell lymphoma, as well as their significance, and recent advances in Notch-targeted therapies.
Highlights
The Notch signaling pathway is highly conserved from Drosophila to humans and plays an important role in the regulation of cellular proliferation, differentiation and apoptosis
Activating mutations identified in the T-ALL cluster at the heterodimerization domain (HD) and the proline, glutamine, serine and threonine (PEST) domain led to ligand-independent cleavage of the Notch receptor and a reduced degradation of NICD1, respectively
Increased Notch signaling is linked to hematological malignancies
Summary
Ligase Itch/AIP4 [6] or another ubiquitin ligase, Nedd4 [7], which act together with Numb [8] and Itch/AIP4 to stimulate endocytosis and lysosomal degradation of the Notch receptor [9]. Cis-inhibition of Notch signaling by the DLL1 ligand has been described in Drosophila and mice [11] These investigations have suggested that while expression of ligands on neighboring cells stimulates Notch activation, expression on the same cell as the Notch receptor may have an inhibitory effect [11]. A direct role of Notch activation in T-ALL remained obscure, since only 1% to 3% of patients with T-ALL were found to carry this translocation It was only after the discovery of a high rate of activating mutations that it became clear that Notch expression is linked
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