Abstract
Notch receptors are single-pass transmembrane proteins that play a critical role in cell fate decisions and have been implicated in the regulation of many developmental processes. The human Notch family comprises of four receptors (Notch 1 to 4) and five ligands. Their signaling can regulate extremely basic cellular processes such as differentiation, proliferation and death. Notch is also involved in hematopoiesis and angiogenesis, and increasing evidence suggests that these genes are involved and frequently deregulated in several human malignancies, contributing to cell autonomous activities that may be either oncogenic or tumor suppressive. It was recently proposed that Notch signaling could play an active role in promoting and sustaining a broad spectrum of lymphoid malignancies as well as mutations in Notch family members that are present in several disorders of T- and B-cells, which could be responsible for altering the related signaling. Therefore, different Notch pathway molecules could be considered as potential therapeutic targets for hematological cancers. In this review, we will summarize and discuss compelling evidence pointing to Notch receptors as pleiotropic regulators of hematologic malignancies biology, first describing the physiological role of their signaling in T- and B-cell development and homeostasis, in order to fully understand the pathological alterations reported.
Highlights
The Notch gene was first identified in Drosophila [1] as a key developmental gene [2]
Since Notch 1 is a key factor in T-cell development, it is clear that it has been well investigated in T-cell diseases such as acute lymphoblastic leukemia (T-ALL)
Rosati E and coworkers demonstrated a high expression of Notch 1, Notch 2, JAG1 and JAG2, in malignant B-cells isolated from 25 patients affected by B-cell chronic lymphocytic leukemia (B-CLL) but not in normal B-cells [75]
Summary
The Notch gene was first identified in Drosophila [1] as a key developmental gene [2]. Notch receptors transduce short-range signals by interacting with the transmembrane Delta-like and Jagged ligands on neighboring cells. An ADAM-family metalloprotease called ADAM10, cleaves the receptor just outside the membrane and the Notch extracellular domain (NECD) is released [4] This induces γ-secretase to cleave the transmembrane region at the S3 site, releasing the Notch intracellular domain (NICD) thereby entering the cell nucleus and triggering gene expression [5]. During the transcriptional activation process, NICD is phosphorylated on its PEST domain and targeted for proteasome-mediated degradation by ubiquitin ligases known as FBXW7 This limits the half-life of a canonical Notch signal [8]. Interaction between Notch 1 and its ligands, DLL4 and JAG2, leads γδ T-cell development through the repression of Bcl11b expression [30]. The role of Notch 1 in the differentiation of immune cells makes it a highly studied gene in hematologic malignancies, but it is implicated in a wide range of solid tumors, concerning growth and progression, such as melanoma [37], intrahepatic cholangiocarcinoma [38], prostate cancer [39] and osteosarcoma [40]
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