Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of malignant plasma cells in the bone marrow (BM) 1. Despite recent advances in therapy 2, MM remains incurable, largely due to the emergence and maintenance of drug-resistant myeloma cells 3, whose interactions within the BM microenvironment, the BM myeloma niche, are critical 4. Because Notch signaling, a pathway activated only via cell-cell contacts, has been implicated as an integral part of the onset and progression of MM 5, we investigated how Notch activation in myeloma cells, specifically through interactions with ligand-expressing niche cells, affects the pathophysiology of MM.

We first demonstrated the presence of at least one Notch receptor in 10 arbitrarily selected MM cell lines (Supplementary Figure 1a and b). The presence of these receptors indicates that Notch signaling can be activated and is functional in human myeloma cells. Of the two Notch ligands examined, Jagged1, but not Jagged2, is known to be abundantly expressed in many types of cells in the BM myeloma niche 6, 7. Therefore, we investigated the effects of niche-induced Jagged1-Notch activation on myeloma cells. To distinguish niche-induced Notch activation from the homotypic activation of Notch in myeloma cells, in which Notch and its ligands can be simultaneously expressed, we selected five MM cell lines that expressed Jagged1 weakly or not at all for analyses. Contrary to previous reports 8, the presence of