Transcriptional repressor BCL-6 immortalizes germinal center-like B cells in the absence of p53 function.
Chromosomal rearrangements in non-Hodgkin's B-cell lymphoma implicate BCL-6 as an oncogene, yet direct evidence for BCL-6 acting as an oncogene in B cells has been lacking. Here, we show that BCL-6 can immortalize primary B cells, but only in the absence of p53 tumor suppressor function. The expression of BCL-6 led to greatly increased B-cell proliferation, particularly in response to CD40 stimulation. Furthermore, BCL-6-infected p53-deficient B cells gave rise to immortalized cell lines that could be maintained by CD40 stimulation. We found that in primary mouse B cells, BCL-6 repressed expression of the Blimp-1, p27kip1, and cyclin D2 target genes. BCL-6 did not markedly repress the PDCD2 and BCL-XL target genes. The BCL-6 immortalized cell lines had a phenotype consistent with germinal center B cells, they expressed the germinal center-specific M17 gene, and a significant fraction of the cells stained positive with PNA. Our data indicate that BCL-6 may act to maintain B cells in a germinal center-like state, and repression of Blimp-1 by BCL-6 may be particularly crucial for stabilization of the germinal center phenotype. Our data also suggest that disruption of the p53 pathway may be crucial for the development of BCL-6-expressing B-cell lymphomas.
Kusam
Saritha
S
Department of Microbiology and Immunology and The Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Vasanwala
Farha H
FH
Dent
Alexander L
AL
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D001483:Base Sequence; D019013:CD40 Antigens / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D019013:CD40 Antigens; D017931:DNA Primers; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53