Notch signaling: its roles and therapeutic potential in hematological malignancies

Abstract

Notch is a highly conserved signaling system that allows neighboring cells to communicate, thereby controlling their differentiation, proliferation and apoptosis, with the outcome of its activation being highly dependent on signal strength and cell type. As such, there is growing evidence that disturbances in physiological Notch signaling contribute to cancer development and growth through various mechanisms. Notch was first reported to contribute to tumorigenesis in the early 90s, through identification of the involvement of the Notch1 gene in the chromosomal translocation t(7;9)(q34;q34.3), found in a small subset of T-cell acute lymphoblastic leukemia. Since then, Notch mutations and aberrant Notch signaling have been reported in numerous other precursor and mature hematological malignancies, of both myeloid and lymphoid origin, as well as many epithelial tumor types. Of note, Notch has been reported to have both oncogenic and tumor suppressor roles, dependent on the cancer cell type. In this review, we will first give a general description of the Notch signaling pathway, and its physiologic role in hematopoiesis. Next, we will review the role of aberrant Notch signaling in several hematological malignancies. Finally, we will discuss current and potential future therapeutic approaches targeting this pathway.

High expression of CPNE3 predicts adverse prognosis in acute myeloid leukemia

“…Of note, several important tumorigenic pathways were significantly upregulated, including “ERBB signaling pathway,” “JAK/STAT signaling pathway,” “glycolysis/gluconeogenesis,” “VEGF signaling pathway” and “Notch signaling pathway” (Fig. f) …”

Molecular and proteomic insight into Notch1 characterization in hepatocellular carcinoma

“…In an effort to bring scientific knowledge from the bench to the bedside, several anti-Notch1 agents are under investigation [27] and it's of important interest to identify molecular biomarkers that can be used to predict tumor response or resistance to therapy. In this study, we used a proteomic approach comparing HepG2 and HepG2 Notch1 depleted cells to identify potential proteins biomarkers for predicting the efficacy of Notch1 inhibition.…”

Notch Signaling in Development, Tissue Homeostasis, and Disease

“…Blocking of Jagged1 prevented and reversed lung goblet cell metaplasia in mouse models (and these effects were enhanced when Jagged2 was simultaneously inhibited), raising the provocative possibility that such treatments might be clinically deployed for respiratory disease characterized by excess mucus secretions (384). In addition to antibodies to receptors and ligands, antibodies to Nicastrin have been explored preclinically (190,263), although they, like GSIs, are likely to affect all ␥-secretase-cleaved proteins (244). Antibodies can also be used for GVHD, with few reported side effects (723; for review, see Ref.…”