BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma

ates survival, proliferation, and differentia-tion blockade of B cells during the germinal-centerreactionandisfrequentlymisregulated in B-cell non-Hodgkin lymphoma (BNHL). The p53 tumor-suppressor gene is cen-tral to tumorigenesis. Microarray analysis identified BCL6 as a primary target of p53. The BCL6 intron 1 contains a region in which 3 types of genetic alterations are frequent in BNHL: chromosomal transloca-tions, point mutations, and internal dele-tions. We therefore defined it as TMDR (translocations, mutations, and deletions re-gion). The BCL6 gene contains a p53 re-sponse element (p53RE) residing within the TMDR. This p53RE contains a motif known to be preferentially targeted by somatic hy-permutation. This p53RE is evolutionarily conserved only in primates. The p53 protein binds to this RE in vitro and in vivo. Reporter assays revealed that the BCL6 p53RE can confer p53-dependent transcriptional activa-tion. BCL6 mRNA and protein levels in-creased after chemotherapy/radiotherapy in human but not in murine tissues. The in-crease in BCL6 mRNAlevels was attenuated by the p53 inhibitor PFT-. Thus, we define the BCL6 gene as a new p53 target, regu-lated through a RE frequently disrupted i