Regulation of BCL6 expression in B cell development and lymphomagenesis
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BCL6 is the most frequently translocated proto-oncogene in diffuse large B cell lymphomas (DLBCLs). It encodes a potent transcription repressor that is specifically expressed and critically required at the germinal center (GC) stage of B cell development. Deregulated expression of BCL6 plays a key role in the pathogenesis of DLBCLs. Therefore, elucidating mechanisms governing BCL6 expression should significantly improve our understanding of the GC reaction and the pathogenesis of DLBCLs.;Previous studies have shown that chromosomal translocations and somatic hypermutations targeting the 5' regulatory region of BCL6 are the most frequent abnormalities associated with DLBCLs. Nevertheless, at the onset of our work, very little was known about how BCL6 transcription is regulated in normal B cells and deregulated in lymphomas. In the first part of my thesis work, a negative feedback mechanism that normally regulates BCL6 transcription is identified which maintains BCL6 at a level appropriate for its biological functions in normal B cells, while in lymphomas, DLBCL-associated translocations and "activating mutations" deregulate BCL6 expression by bypassing this negative autoregulation.;In GC B cells where the highest levels of BCL6 are detected, we hypothesized that there must be nuclear factor(s) capable of increasing the threshold of BCL6 autoregulation. I have examined the potential roles of transcription factors C/EBPalpha, C/EBPbeta, and PU.1 in BCL6 expression in GC-derived B cell lines but my results argue against major roles of these proteins.;In collaborative studies of novel BCL6 target genes, I investigated gene expression changes in BCL6 knock-out mice and inducible BCL6 cell lines and have uncovered evidence that BCL6 functionally interacts with components of the NF-kappaB and IL-6/STAT3 pathways. Together with findings generated by other colleagues in the lab, we demonstrated that BCL6 can control cell proliferation by negatively regulating NF-kappaB and IL-6/STAT3 signaling.;In conclusion, my results establish a model of negative autoregulation of BCL6 expression. Continued investigation is needed to uncover nuclear factor(s) capable of relaxing threshold of this regulation in normal GC B cells. Other results from collaborative studies have shown that an important aspect of BCL6 function is carried out through functional interaction with cell signaling pathways.
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