| Entity | Multiple Myeloma |
| Disease | The NOTCH ligand, JAG2, has been found to be overexpressed in malignant plasma cells from multiple myeloma (MM) patients and cell lines but not in nonmalignant plasma cells from tonsils, bone marrow from healthy individuals, or patients with other malignancies. Since MM cells have been shown to induce IL-6 expression in stromal cells in a largely cell contact-dependent manner, it has been concluded that MM cells induce production of IL-6 in stromal cells through overexpression of JAG2. Once secreted, IL-6 enhances proliferation of myeloma cells in a paracrine fashion. |
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| Schematic representation of the physiological activation of NOTCH, with Cell 1 (MM plasma cell) expressing JAG2 and Cell 2 (Stromal cell) NOTCH.
A: JAG2 binds NOTCH via cell-to-cell contact.
B: Binding of JAG2 induces a proteolytic cleavage of the intracellular part of NOTCH (NOTCH-IC).
C: Once cleaved, NOTCH-IC is translocated into the nucleus.
D: Once in the nucleus, NOTCH-IC will be able to bind to downstream effectors such as CBF1, to activate, for example, the IL-6 gene transcription. |
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| Oncogenesis | The induction of IL-6 secretion has been blocked in vitro by interference with anti-Notch-1 monoclonal antibodies raised against the binding sequence of Notch-1 with JAG2. Taken together, these results indicate that JAG2 over expression may be an early event in the pathogenesis of multiple myeloma involving IL-6 production. |
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| The Jagged2 gene maps to chromosome 12 and is a candidate for the lgl and sm mutations. |
| Lan Y, Jiang R, Shawber C, Weinmaster G, Gridley T |
| Mammalian genome : official journal of the International Mammalian Genome Society. 1997 ; 8 (11) : 875-876. |
| PMID 9341252 |
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| Human ligands of the Notch receptor. |
| Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, Leiman J, Ward D, Ish-Horowitz D, Artavanis-Tsakonas S |
| The American journal of pathology. 1999 ; 154 (3) : 785-794. |
| PMID 10079256 |
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| Characterization, chromosomal localization, and the complete 30-kb DNA sequence of the human Jagged2 (JAG2) gene. |
| Deng Y, Madan A, Banta AB, Friedman C, Trask BJ, Hood L, Li L |
| Genomics. 2000 ; 63 (1) : 133-138. |
| PMID 10662552 |
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| Mouse Jagged2 is differentially expressed in hematopoietic progenitors and endothelial cells and promotes the survival and proliferation of hematopoietic progenitors by direct cell-to-cell contact. |
| Tsai S, Fero J, Bartelmez S |
| Blood. 2000 ; 96 (3) : 950-957. |
| PMID 10910909 |
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| The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent gamma-secretase cleavage. |
| Ikeuchi T, Sisodia SS |
| The Journal of biological chemistry. 2003 ; 278 (10) : 7751-7754. |
| PMID 12551931 |
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| Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. |
| Houde C, Li Y, Song L, Barton K, Zhang Q, Godwin J, Nand S, Toor A, Alkan S, Smadja NV, Avet-Loiseau H, Lima CS, Miele L, Coignet LJ |
| Blood. 2004 ; 104 (12) : 3697-3704. |
| PMID 15292061 |
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