BCL6 cooperates with CD40 stimulation and loss of p53 function to rapidly transform primary B cells.
The BCL6 transcriptional repressor protein has been shown to promote B-cell lymphoma in transgenic mouse models. The mechanism by which BCL6 transforms primary B cells is unclear, although repression of the p53 tumor suppressor is thought to play a role. Here, we showed that BCL6 has critical oncogene functions that are independent of p53 repression. We found that BCL6 cooperates with constitutive CD40 signaling to rapidly transform p53-deficient primary mouse B cells in vitro. Constitutive CD40 signaling alone does not transform p53-deficient B cells, indicating that BCL6 acts specifically as an immortalizing oncogene in this system. The BCL6 transformed B cells are polyclonal and form polyclonal tumors. At the initiation of the cultures, BCL6 does not significantly alter cell cycle progression, but it does promote increased cell survival. Early cultures of BCL6-expressing B cells exhibited marked repression of ATR and p27kip1 but not other BCL6 target genes, suggesting that the ATR and p27kip1 genes have key early roles in mediating BCL6 transformation function. BCL6-transformed cell lines exhibited further decreases of ATR and p27kip1 expression plus strong decreases in Blimp1 and PDCD2 expression. Our study provides important clues about the critical target genes used by BCL6 to transform primary B cells and indicates that the CD40 signaling pathway can collaborate with BCL6 in the transformation of primary B cells. Thus, our study demonstrates a rapid in vitro system to analyze the transformation function of BCL6.
Kusam
Saritha
S
Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Munugalavadla
Veerendra
V
Sawant
Deepali
D
Dent
Alexander
A
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D016393:Lymphoma, B-Cell / Q000473:pathology; D051379:Mice; D051560:Proto-Oncogene Proteins c-bcl-6; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C490010:Bcl6 protein, mouse; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D016159:Tumor Suppressor Protein p53; D023201:CD40 Ligand