Gp130 and ras mediated signaling in human plasma cell line INA-6: a cytokine-regulated tumor model for plasmacytoma

Burger, Renate; Guenther, Andreas; Bakker, Frank; Schmalzing, Marc; Bernand, Sabrina; Baum, Wolfgang; Duerr, Birgit; Hocke, Gertrud M.; Steininger, H; Gebhart, Erich; Gramatzki, Martin

doi:10.1038/sj.thj.6200075

Cited by 94 publications

(143 citation statements)

References 38 publications

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“…The multiple myeloma cell lines used in this study were INA-6 (kind gift from Dr Martin Gramatzki, Erlangen, Germany) 27 and IH-1. 14 INA-6 cells were grown in 10% heat inactivated fetal calf serum in RPMI-1640 (hereafter described as RPMI) supplemented with recombinant human interleukin (IL)-6 (1 ng/ml) (Biosource, Camarillo, CA, USA).…”

Section: Cell Culture and Reagentsmentioning

confidence: 99%

Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC

et al. 2011

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Bone morphogenetic proteins (BMPs) have been shown to induce apoptosis and growth arrest in myeloma cells. However, the molecular mechanisms behind these events are not known. The MYC oncogene is a master regulator of cell growth and protein synthesis and MYC overexpression has been proposed to be associated with the progression of multiple myeloma. Here, we show that BMP-induced apoptosis in myeloma cells is dependent on downregulation of MYC. Moreover, the results suggest that targeting the MYC addiction in multiple myeloma is an efficient way of killing a majority of primary myeloma clones. We also found that myeloma cells harboring immunoglobulin (IG)-MYC translocations evaded BMP-induced apoptosis, suggesting a novel way for myeloma cells to overcome potential tumor suppression by BMPs.

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Section: Cell Culture and Reagentsmentioning

confidence: 99%

Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC

et al. 2011

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“…Interleukin (IL)-6 is known to play an essential role in the proliferation and survival of MM cells (Klein et al, 1995). In the human IL-6-dependent MM cell line INA-6 (Burger et al, 2001), we recently demonstrated that IL-6 promotes survival through an as yet unknown antiapoptotic pathway that required the activation of signal transducer and activator of transcription 3 (Stat3) (Brocke-Heidrich et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Brocke-Heidrich

Cvijic

et al. 2006

Oncogene

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BCL3 is a proto-oncogene affected by chromosomal translocations in some patients with chronic lymphocytic leukemia. It is an IjB family protein that is involved in transcriptional regulation of a number of NF-jB target genes. In this study, interleukin (IL)-6-induced BCL3 expression and its effect on survival of multiple myeloma (MM) cells were examined. We demonstrate the upregulation of BCL3 by IL-6 in INA-6 and other MM cell lines. Sequence analysis of the BCL3 gene locus revealed four potential signal transducer and activator of transcription (Stat) binding sites within two conserved intronic enhancers regions: one located within enhancer HS3 and three within HS4. Chromatin immunoprecipitation experiments showed increased Stat3 binding to both enhancers upon IL-6 stimulation. Silencing Stat3 expression by small interfering RNA (siRNA) abrogated BCL3 expression by IL-6. Using reporter gene assays, we demonstrate that BCL3 transcription depends on HS4. Mutation of the Stat motifs within HS4 abolished IL-6-dependent BCL3 induction. Furthermore, BCL3 transcription was inhibited by its own gene product. This repressive feedback is mediated by NF-jB sites within the promoter and HS3. Finally, we show that overexpression of BCL3 increases apoptosis, whereas BCL3-specific siRNA does not affect the viability of INA-6 cells suggesting that BCL3 is not essential for the survival of these cells.

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“…9 The survival of INA-6 cells in vitro is strictly dependent on exogenous IL-6 without growth response to other gp130 cytokines. With the establishment of a xenograft model in severe combined immune deficiency (SCID) mice using INA-6, a non-optimal environment devoid of human IL-6 was provided.…”

Section: 8mentioning

confidence: 99%

Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth

et al. 2016

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IntroductionMultiple myeloma (MM) is characterized by the expansion of clonal plasma cells within the bone marrow (BM), leading to an M-protein in serum, antibody deficiency, and skeletal destruction. Despite stem cell transplantation and novel therapies, the vast majority of patients with MM will eventually relapse and become refractory to standard therapy. Treatment strategies specifically targeting mechanisms of tumor growth and survival are being intensely explored in MM in order to improve © Ferrata Storti Foundation patient outcome. 1In the pathogenesis of MM, genetic changes drive the development of the malignant clone, but the interaction between the malignant plasma cells and the BM microenvironment has been shown to be equally important in mediating myeloma cell survival and progression.2 One of the established pathogenic key factors produced in the BM milieu is interleukin(IL)-6, which promotes the growth and survival of the malignant plasma cells and mediates drug resistance.3 While some myeloma cells produce their own IL-6, 4 bone marrow stromal cells (BMSCs) are the main source, establishing a strong paracrine growth stimulation. 5 Other sources of IL-6 in MM are macrophages, osteoblasts and osteoclasts; 2 eosinophils and megakaryocytes may also contribute. 6The receptor for IL-6 comprises a specific α-receptor, glycoprotein (gp) 80 (CD126), which, after ligand binding, recruits the gp130 receptor (IL6ST, CD130). Gp130 is the common signal transducer for a family of cytokines with pleiotropic and partly redundant activities.7 While signaling via IL-6 and IL-11 is initiated via gp130 homodimerization, the receptor complexes of other family members consist of heterodimers of gp130 with a second signaling molecule, most of which use the leukemia inhibitory factor receptor (LIFR). Leukemia inhibitory factor (LIF) and oncostatin M (OSM) directly induce gp130/LIFR heterodimerization without the involvement of other receptor components. Upon dimerization, associated Janus kinases (JAKs) become activated and phosphorylate specific tyrosine residues on the receptors, which serve as docking sites for transcription factors and adaptor proteins. The main signaling pathways induced by gp130 are the activation of STAT (signal transducer and activator of transcription)-3, the Ras-dependent mitogen-activated protein kinase (MAPK) cascade, and the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway. 7,8The human plasma cell line INA-6 was generated in our laboratory from the pleural effusion of a patient with advanced plasma cell disease. 9 The survival of INA-6 cells in vitro is strictly dependent on exogenous IL-6 without growth response to other gp130 cytokines. With the establishment of a xenograft model in severe combined immune deficiency (SCID) mice using INA-6, a non-optimal environment devoid of human IL-6 was provided. Despite the fact that murine IL-6 is not active on human cells, plasma cell tumors developed over a period of up to five months. In serum and ascites of tumor-beari...

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Gp130 and ras mediated signaling in human plasma cell line INA-6: a cytokine-regulated tumor model for plasmacytoma

Cited by 94 publications

References 38 publications

Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC

Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth

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