Article

High expression of BCL3 in human myeloma cells is associated with increased proliferation and inferior prognosis

Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
European Journal Of Haematology (Impact Factor: 2.41). 02/2009; 82(5):354-63. DOI: 10.1111/j.1600-0609.2009.01225.x
Source: PubMed

ABSTRACT BCL3 is a putative oncogene encoding for a protein belonging to the inhibitory kappaB-family. We experienced that this putative oncogene was a common target gene for growth-promoting cytokines in myeloma cell lines.
Gene expression of BCL3 was studied in 351 newly diagnosed myeloma patients, 12 patients with smouldering myeloma, 44 patients with monoclonal gammopathy of undetermined significance and 22 healthy individuals. Smaller material of samples was included for mRNA detection by RT-PCR, protein detection by Western blot and immunohistochemistry, and for cytogenetic studies. A total of eight different myeloma cell lines were studied.
Bcl-3 was induced in myeloma cell lines by interleukin (IL)-6, IL-21, IL-15, tumor necrosis factor-alpha and IGF-1, and its upregulation was associated with increased proliferation of the cells. In a population of 351 patients, expression levels of BCL3 above 75th percentile were associated with shorter 5-yr survival. When this patient population was divided into subgroups based on molecular classification, BCL3 was significantly increased in a poor risk subgroup characterized by overexpression of cell cycle and proliferation related genes. Intracellular localization of Bcl-3 was dependent on type of stimulus given to the cell.
BCL3 is a common target gene for several growth-promoting cytokines in myeloma cells and high expression of BCL3 at the time of diagnosis is associated with poor prognosis of patients with multiple myeloma (MM). These data may indicate a potential oncogenic role for Bcl-3 in MM.

Download full-text

Full-text

Available from: Torstein Baade Ro, Aug 13, 2015
1 Follower
 · 
227 Views
  • Source
    • "Of note, the rearranged bcl-3 gene remains intact but is transcriptionally activated, resulting in overproduction of the Bcl-3 protein and presumably elevated transactivation activity of the p50 or p52 complexes. Overproduction of Bcl-3 independent of its gene translocation has also been observed in various tumors including breast cancer, colorectal cancer, hepatocellular carcinoma , melanoma, nasopharyngeal carcinoma, and different lymphomas [69] [70] [71] [72] [73] [74]. In fact, overexpression of Bcl-3 is often associated with tumor progression and poor prognosis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies have clearly linked nuclear factor-kappaB (NF-κB), a transcription factor that plays a central role in regulating immune and inflammatory responses, to tumor development, progression, and metastasis as well as tumor therapy resistance. However, it still remains largely unknown on how the tightly regulated NF-κB becomes constitutively activated in tumorigenesis and how the original cancer immunosurveillance function of NF-κB is transformed to be tumorigenic. To address these important issues for cancer prevention and treatment, we discuss current understanding of the molecular mechanisms and molecules involved in the oncogenic activation of NF-κB. We also discuss current understanding of how NF-κB coordinates the inflammatory and malignant cells in tumorigenesis.
    American Journal of Cancer Research 01/2011; 1(2):192-221. · 3.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lactoferrin (LF) plays pivotal roles in primary defense against microbial infection and other cellular processing including immuno-modulation and growth stimulation of cells. To understand the molecular mechanism of LF action we stably overexpressed LF in the K562 erythroleukemia cells and examined differential gene expression using a cDNA microarray. One of the genes that were highly upregulated in the LF-overexpressing cells was the IκB family member B cell lymphoma-3 (BCL-3) that is implicated to promote B cell proliferation and chronic lymphocytic leukemia. Northern blot as well as RT-PCR analysis confirmed that BCL-3 was highly induced in LF-transfected cells. Furthermore, by treating the K562 cells with natural LF protein, we observed a significant increase of BCL-3 messages with the peak at 50 μg/mL and 2 h after treatment. These results suggest that LF signals to induce BCL-3 and thereby promotes B cell proliferation and survival.
    BioChip journal 12/2011; 5(4). DOI:10.1007/s13206-011-5410-y · 1.05 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We hypothesized that fusing granulocyte-macrophage colony-stimulation factor (GMCSF) and interleukin (IL)-21 as a single bifunctional cytokine (hereafter GIFT-21) would lead to synergistic anticancer immune effects because of their respective roles in mediating inflammation. Mechanistic analysis of GIFT-21 found that it leads to IL-21Ralpha-dependent STAT3 hyperactivation while also contemporaneously behaving as a dominant-negative inhibitor of GMCSF-driven STAT5 activation. GIFT-21's aberrant interactions with its cognate receptors on macrophages resulted in production of 30-fold greater amounts of IL-6, TNF-alpha, and MCP-1 when compared to controls. Furthermore, GIFT-21 treatment of primary B and T lymphocytes leads to STAT1-dependent apoptosis of IL-21Ralpha(+) lymphocytes. B16 melanoma cells gene-enhanced to produce GIFT-21 were immune rejected by syngeneic C57Bl/6 mice comparable to the effect of IL-21 alone. However, a significant GIFT-21-driven survival advantage was seen when NOD-SCID mice were implanted with GIFT-21-secreting B16 cells, consistent with a meaningful role of macrophages in tumor rejection. Because GIFT-21 leads to apoptosis of IL-21Ralpha(+) lymphocytes, we tested its cytolytic effect on IL-21Ralpha(+) EL-4 lymphoma tumors implanted in C57Bl/6 mice and could demonstrate a significant increase in survival. These data indicate that GIFT-21 is a novel IL-21Ralpha agonist that co-opts IL-21Ralpha-dependent signaling in a manner permissive for targeted cancer immunotherapy.
    Molecular Therapy 04/2010; 18(7):1293-301. DOI:10.1038/mt.2010.49 · 6.43 Impact Factor
Show more

Similar Publications