Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In multiple myeloma (MM), the growth of primary plasma cells depends not only on interleukin-6 (IL-6), but also on additional unidentified signals delivered by the bone marrow environment. Using Atlas complementary DNA (cDNA) arrays comprising 268 genes coding for intercellular signaling molecules, this study identified genes that are overexpressed in myeloma cells compared to autologous B-lymphoblastoid cell lines. These genes encode the oncogenic Tyro3 tyrosine kinase receptor, the heparin-binding epidermal growth factor-like growth factor (HB-EGF) that is an epithelial autocrine tumor growth factor, the thrombin receptor (TR) that is linked to HB-EGF and syndecan-1 processing and to cell invasion, chemokine receptors CCR1 and CCR2, the Wnt pathway actor Frizzled-related protein (FRZB), and the Notch receptor ligand Jagged 2. These data, obtained with the Atlas cDNA array, were confirmed by reverse transcriptase-polymerase chain reaction or protein analysis or both. Furthermore, Tyro3, HB-EGF, TR, and FRZB gene expression was documented in purified primary malignant plasma cells from patients with plasma cell leukemia or MM. HB-EGF and FRZB were poorly expressed in purified polyclonal plasma cells. Finally, HB-EGF was proved to be an essential autocrine growth factor for the XG-1 myeloma cells. This study shows the potency and the biologic relevance of cDNA arrays used to analyze simultaneously a large panel of intercellular signaling genes and, by identifying several genes overexpressed in malignant plasma cells, opens new fields of investigation in MM biology. (Blood. 2001;98:771-780)
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PMID:Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays. 1146 78

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.
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PMID:Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. 1529 61

Although Notch receptor expression on malignant B cells is widespread, the effect of Notch signaling in these cells is poorly understood. To investigate Notch signaling in B-cell malignancy, we assayed the effect of Notch activation in multiple murine and human B-cell tumors, representing both immature and mature subtypes. Expression of constitutively active, truncated forms of the 4 mammalian Notch receptors (ICN1-4) inhibited growth and induced apoptosis in both murine and human B-cell lines but not T-cell lines. Similar results were obtained in human precursor B-cell acute lymphoblastic leukemia lines when Notch activation was achieved by coculture with fibroblasts expressing the Notch ligands Jagged1 or Jagged2. All 4 truncated Notch receptors, as well as the Jagged ligands, induced Hes1 transcription. Retroviral expression of Hairy/Enhancer of Split-1 (Hes1) recapitulated the Notch effects, suggesting that Hes1 is an important mediator of Notch-induced growth arrest and apoptosis in B cells. Among the B-cell malignancies that were susceptible to Notch-mediated growth inhibition/apoptosis were mature B-cell and therapy-resistant B-cell malignancies, including Hodgkin, myeloma, and mixed-lineage leukemia (MLL)-translocated cell lines. These results suggest that therapies capable of activating Notch/Hes1 signaling may have therapeutic potential in a wide range of human B-cell malignancies.
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PMID:Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies. 1611 16

Multiple myeloma (MM) is a clonal B-cell neoplasm that accounts for 10% of all malignant hematologic neoplasms and that affects terminally differentiated B cells (i.e., plasma cells). It is now well recognized that the cytokine interleukin-6 (IL-6) is a major cytokine that promotes the proliferation of malignant plasma cells in MM. The IL-6 gene can be regulated by the NOTCH genes products. We have previously shown that the NOTCH ligand, JAG2, is overexpressed in MM. To investigate the mechanism(s) leading to JAG2 overexpression in MM, we assessed potential epigenetic modifications of the JAG2 promoter. We showed that the JAG2 promoter region is aberrantly acetylated in MM cell lines and patient samples. The acetylation state of histones is regulated by the recruitment of histone deacetylases (HDAC). HDACs are typically recruited to promoter regions through interaction with nuclear corepressors such as SMRT. SMRT levels were therefore investigated. Interestingly, MM cell lines and patient samples presented significantly reduced SMRT levels. The experiments suggest a correlation between constitutive acetylation of the JAG2 core promoter in the MM cell lines and reduced levels of the SMRT corepressor that recruits HDAC to promoter regions. Finally, SMRT function restoration induced JAG2 down-regulation as well as MM cell apoptosis.
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PMID:Loss of the SMRT/NCoR2 corepressor correlates with JAG2 overexpression in multiple myeloma. 1941 36

Notch signaling pathway is a main pathway through cell-cell interactions, which regulates the programmed cell death, cellular proliferation and differentiation in multiple cell systems, and also is an important signaling pathway to modulate the balance between proliferation and differentiation in hematopoietic environment, and is related with the incidence of multiple hematologic malignancies. Multiple myeloma (MM) is malignant in B cell lineage and characterized by clonal proliferative plasma cells. It is very difficult to cure MM patients with a low proliferation rate of the MM cell and drug resistance to the standard dosage of chemotherapy. In recent years, research has shown that in the malignant plasma cells of the patients with multiple myeloma (MM) and the cell lines, but not in normal plasma cells or tumor cells from patients with other malignancies, the Notch ligand Jagged2 was found to be overexpressed. Jagged2 can induce stromal cells to secrete IL-6, VEGF and IGF-1. Notch activation can interact with NF-kappaB and C-myc to promote the proliferation and to inhibit the apoptosis of MM cells, showing in the relationship between the incidence of myeloma and drug resistance. Inhibition of the Notch signaling pathway may induce the apoptosis of MM cells and enhance the effect of chemotherapy. Study indicated that the specific inhibition of Notch signaling by treatment with a gamma-secretase inhibitor (GSI) alone, a specific pharmacologic inhibitor of Notch signaling, induces the apoptosis of myeloma cells and improves sensitivity of myeloma cell to chemotherapy when combined. In this article the composition of Notch signalling pathway, the mechanism of Notch signalling pathway and the relation of Notch signalling pathway to multiple myeloma were reviewed.
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PMID:[Notch signaling pathway and multiple myeloma]. 1984 Apr 88

In order to investigate the mechanisms of phenylhexyl isothiocyanate (PHI) inhibiting the proliferation of multiple myeloma cell RPMI8226 in vitro, the RPMI8226 cells were co-cultured with PHI of various concentrations. The inhibition of proliferation was measured by MTT test and the cell apoptosis was assayed by DAPI staining. The changes of Notch1, Jagged2, BCL-2 and p-Akt proteins in the PHI-treated cells were detected by Western blot. The results showed that PHI inhibited RPMI8226 cell proliferation in certain concentration range and induced their apoptosis. The inhibiting effect caused by PHI showed a concentration-and time-dependent manner. The PHI decreased expressions of Notch1 and Jagged2 proteins in a concentration-and time-dependent manners, the levels of BCL-2 and p-Akt declined at the same time. It is concluded that PHI can inhibit proliferation of RPMI8226 cells, and induce their apoptosis. The cell apoptosis is associated with the inhibition of Notch signaling and downstream targets BCL-2 and p-Akt proteins of RPMI8226 cells, PHI may be a new Notch signaling inhibitor and a promising therapeutic drug for multiple myeloma.
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PMID:[Inhibitory effect of phenylhexyl isothiocyanate on notch signaling of multiple myeloma cells in vitro]. 2186 19

The purpose of this study was to identify the pathways associated with the ability of CD138(+) human myeloma cells to form colonies in a serum-free semi-solid human collagen-based assay. Only 26% (7 of 27) of human myeloma cell lines were able to spontaneously form colonies. This spontaneous clonogenic growth correlated with the expression of the NOTCH ligand JAG2 (p<0.001). Blocking JAG-NOTCH interactions with NOTCH-Fc chimeric molecules impaired self-colony formation, indicating a role for JAG-NOTCH pathway in colony formation. In two cell lines, silencing of JAG2 blocked both colony formation and in vivo tumor formation in immunocompromised mice. RT-PCR and flow cytometry analysis revealed that JAG2 is often expressed by CD138(+) primary cells. Our results indicate that spontaneous clonogenic growth of myeloma cells requires the expression of JAG2.
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PMID:Critical role of the NOTCH ligand JAG2 in self-renewal of myeloma cells. 2234 62

This study was aimed to investigate the molecular mechanism of doxorubicin resistance in multiple myeloma cell line and certify the effect of Notch signal over-expression on drug resistance of myeloma cells. The doxorubicin RPMI 8226 cell line (RPMI8226/DOX) was established by culturing 8226 cells with continuous low concentration and intermittent gradually-increasing-concentration of doxorubicin in vitro, the mRNA expression of Notch2,Jagged1, Jagged2, HES1 were measured by RT-PCR and the P-170 protein expression was detected by Western blot in RPMI 8226 cell line; the changes of IL-6 and VEGF were tested by ELISA. The results showed that the Notch mRNA expression (Notch2, Jagged1, Jagged2 increased gradually along with the increase of chemotherapeutic drug resistance, but the expression of HESI mRNA gradually decreased along with the increase of drug resistance. The expression level of P-170 protein was upregulated gradually along with the increase of drug resistance. The level of VEGF and IL-6 in culture supernatants of RPMI8226/DOX was higher than that in RPMI 8226. It is concluded that the establishment of RPMI 8226/DOX cell line is a useful model to analyze the mechanism of chemotherapeutic drug resistance in multiple myeloma, Notch activation is closely correlated with the drug resistance of multiple myeloma and Notch signaling may to be used as a new target for multiple myeloma treatment.
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PMID:[Molecular mechanism of Doxorubicin resistance in multiple myeloma cell line]. 2533 84

Multiple myeloma (MM) is an incurable plasma cell malignancy arising primarily within the bone marrow (BM). During MM progression, different modifications occur in the tumor cells and BM microenvironment, including the angiogenic shift characterized by the increased capability of endothelial cells to organize a network, migrate and express angiogenic factors, including vascular endothelial growth factor (VEGF). Here, we studied the functional outcome of the dysregulation of Notch ligands, Jagged1 and Jagged2, occurring during disease progression, on the angiogenic potential of MM cells and BM stromal cells (BMSCs). Jagged1-2 expression was modulated by RNA interference or soluble peptide administration, and the effects on the MM cell lines' ability to induce human pulmonary artery cells (HPAECs) angiogenesis or to indirectly increase the BMSC angiogenic potential was analyzed in vitro; in vivo validation was performed on a zebrafish model and MM patients' BM biopsies. Overall, our results indicate that the MM-derived Jagged ligands (1) increase the tumor cell angiogenic potential by directly triggering Notch activation in the HPAECs or stimulating the release of angiogenic factors, i.e., VEGF; and (2) stimulate the BMSCs to promote angiogenesis through VEGF secretion. The observed pro-angiogenic effect of Notch activation in the BM during MM progression provides further evidence of the potential of a therapy targeting the Jagged ligands.
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PMID:Jagged Ligands Enhance the Pro-Angiogenic Activity of Multiple Myeloma Cells. 3293 49