Notch1–JAG1 signaling induces aggressive myeloma cell behaviors

抄録

The Notch signaling pathway plays a crucial role in the tumor microenvironment. We examined the expression of Notch receptors (Notch1, Notch2, Notch3, and Notch4) and its ligands (JAG1, JAG2, DLL1, DLL3, and DLL4) in multiple myeloma (MM) cells and the functions of Notch signaling in disease progression. NOTCH1, NOTCH2, and JAG1 mRNA were highly expressed in 17 MM cell lines and primary MM cells from 28 patients, although mRNA levels of NOTCH1 were significantly lower than those of NOTCH2. However, anti-Notch1 antibody inhibited MM cell proliferation and increased the percentage of bortezomib-induced apoptotic MM cells as compared with isotype control and cells cultured with anti-Notch2 antibody. Furthermore, Notch1⁺ MM cells showed greater proliferative potential and decreased drug susceptibility compared with Notch^– cells. Aggressive disease behaviors in Notch1⁺ MM cells were suppressed by anti-JAG1 antibody. Furthermore, gene expression in Notch1⁺ cells showed upregulation of p21 and CCND1/2 and downregulation of apoptotic genes compared with those in Notch^– cells. Those results demonstrate that the Notch1–JAG1 signaling pathway confers a high malignant potential, suggesting that its Notch signaling may be specifically associated with MM disease progression.