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

Abstract

BCL3 is a putative oncogene encoding for a protein belonging to the inhibitory κB-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-α 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.