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Page 4 of 15 Sabol et al. J Cancer Metastasis Treat 2021;7:20 https://dx.doi.org/10.20517/2394-4722.2021.35

Figure 1. Activation of the canonical Notch signaling pathway. Notch mediates the transmission of near- range signals by physical
contact between adjacent cells. The sending signal cell expresses Notch ligands that bind to Notch receptors in the receiving signal cell.
Upon binding, the intracellular portion of the Notch receptor undergoes sequential proteolytic cleavage by Adam enzymes and the γ-
secretase complex. The cleavage by the γ-secretase complex frees the Notch intracellular domain (NICD) from the transmembrane
Notch domain and it translocates to the nucleus. In the nucleus, NICD promotes a transcriptional switch by binding to RbpjK and
displacing of co-repressors and promoting the recruitment of MAML proteins and other transcriptional activators, activating the gene
transcription of Notch target genes of the Hes and Hey families.

elevated in malignant plasma cells from MM patients or if it changes as the disease progresses from MGUS
to PCL. Notch receptor 4 expression is low and in some cases undetectable in malignant plasma cells from
MM patients and MM cell lines . The expression of the Notch ligands Jagged 1 and 2, as well as the Notch
[43]
target gene Hes5 has also been reported as elevated in MM patients [40-42,44] . Although some Notch
components are aberrantly expressed in MM, the mechanism behind their dysregulation remains unclear.
One possibility is that the increase in Notch members is due to genetic mutations. For instance, Notch