| The BCL6 proto-oncogene encodes for a BTB/POZ-zinc finger transcriptional repressor that is required for germinal center (GC) formation and is implicated in the pathogenesis of B-cell lymphoma. BCL6 is thought to control a broad range of cellular processes, including lymphocyte activation, differentiation, cell cycle arrest and apoptosis. The precise molecular mechanism of actions of BCL6 in germinal center B-cell development and lymphomagenesis, however, remains elusive.; In this thesis work, BCL6 is reported to suppress genotoxic stress-induced apoptosis and cell-cycle arrest in GC B cells utilizing two distinct mechanisms: (1) BCL6 directly suppresses DNA damage-induced p53-dependent apoptotic response by binding to specific DNA sites within the p53 promoter region and suppressing the expression of the p53 tumor suppressor gene and, (2) BCL6 prevents p53-independent cell-cycle arrest by binding to Miz1 and suppressing, among other genes devoid of BCL6 binding sites, the p21Cip1/WAF1 activation. These findings suggest that a major function of BCL6 is to allow GC B cells to tolerate the physiologic DNA breaks required for immunoglobulin class-switch recombination and somatic hypermutation without inducing a p53-dependent apoptotic response. In addition, by suppressing p53-dependent apoptotic and p21Cip1-mediated cell cycle arrest responses, BCL6 may facilitate the rapid proliferative expansion of GC B cells during the normal immune response, and when deregulated, the pathologic expansion of NHL cells.; Conversely, genotoxic stress is shown to specifically trigger BCL6 degradation via the ubiquitin proteosome pathway. After genotoxic insults, BCL6 is phosphorylated at Ser/Thr-Pro motifs, likely through ATM/ATR pathway, allowing for its interaction with Pin1, a highly conserve peptidyl-prolyl isomerase. Accordingly, Pin1 facilitates DNA damage-induced BCL6 degradation whereas inhibition of Pin1 expression in B cells rescues BCL6 degradation. Consistently, Pin1-deficient mice display increased GC formation after T-cell dependent immunization, analogous to mice constitutively expressing BCL6. These findings identify a novel mechanism of BCL6 regulation in GC B-cell which may be critical during the normal GC-mediated immune response. These results also have implications for the therapeutic treatment of B-cell lymphoma with deregulated BCL6 expression. |
