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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Brenne
Anne-Tove
AT
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Fagerli
Unn-Merete
UM
Shaughnessy
John D
JD
Våtsveen
Thea Kristin
TK
Rø
Torstein Baade
TB
Hella
Hanne
H
Zhan
Fenghuang
F
Barlogie
Bart
B
Sundan
Anders
A
Børset
Magne
M
Waage
Anders
A
D000081242:B-Cell Lymphoma 3 Protein; D016022:Case-Control Studies; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D016207:Cytokines / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D016207:Cytokines; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014157:Transcription Factors