Current views on the role of Notch signaling and the pathogenesis of human leukemia

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.The Notch gene was first described following the observation of Notches on the wings of fruit flies (Drosophila melanogaster) caused by partial loss of function of the Notch gene. Notch signaling is involved in many biological processes, ranging from embryonic development to cell proliferation and survival. It has been demonstrated that the Notch signaling pathway is involved in vascular formation and morphogenesis during vascular development. Notch1, Notch2 and Notch4 and its ligands (Jagged1, Jagged2, Dll1 and Dll4) are expressed in vascular endothelium, whereas Notch3 is expressed in vascular smooth muscle cells. Mutations in Notch3 are associated with CADASIL syndrome (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), the human degenerative vascular disease.The human Notch family includes four receptors and five ligands [1,2]. All four Notch receptors are synthesized as a single transmembrane polypeptide in the endoplasmic reticulum and transported to the cell surface trough the trans-Golgi network. Notch receptors are expressed as heterodimeric proteins with extracellular, transmembrane and intracellular domains (Figure 1). When a ligand of the Delta/Serrate/LAG-2 family (located on the surface of neighboring cells) binds to the extracellular domain of the Notch receptor, it triggers proteolytic cleav