Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines.
The NOTCH ligand, JAG2, was 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. In addition, JAG2 overexpression was detected in 5 of 5 patients with monoclonal gammopathy of undetermined significance (MGUS), an early phase of myeloma disease progression. This overexpression appears to be a consequence of hypomethylation of the JAG2 promoter in malignant plasma cells. An in vitro coculture assay was used to demonstrate that JAG2 induced the secretion of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and insulin-like growth factor-1 (IGF-1) in stromal cells. Further, the induction of IL-6 secretion was 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 overexpression may be an early event in the pathogenesis of multiple myeloma involving IL-6 production.
Department of Pathology, Loyola University Medical Center, Cardinal Bernardin Cancer Center, Maywood, IL, USA.
Christiane
C
Houde
Yulin
Y
Li
Lynda
L
Song
Kevin
K
Barton
Qing
Q
Zhang
John
J
Godwin
Sucha
S
Nand
Amir
A
Toor
Serhan
S
Alkan
N Veronique
NV
Smadja
Hervé
H
Avet-Loiseau
Carmen S
CS
Lima
Lucio
L
Miele
Lionel J
LJ
Coignet
D002450:Cell Communication; D018920:Coculture Techniques; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6 / Q000378:metabolism; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D009101:Multiple Myeloma / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D010950:Plasma Cells / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; C490504:JAG2 protein, human; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I