In some organisms, small RNA pathways can act nonautonomously, with responses spreading from cell to cell.

The BCL6 transcriptional repressor mediates survival, proliferation, and differentiation blockade of B cells during the germinalcenter reaction and is frequently misregulated in B-cell non-Hodgkin lymphoma (BNHL). The p53 tumor-suppressor gene is central 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 translocations, point mutations, and internal deletions. We therefore defined it as TMDR (translocations, mutations, and deletions region). The BCL6 gene contains a p53 response element (p53RE) residing within the TMDR. This p53RE contains a motif known to be preferentially targeted by somatic hypermutation. 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 activation. BCL6 mRNA and protein levels increased after chemotherapy/radiotherapy in human but not in murine tissues. The increase in BCL6 mRNA levels was attenuated by the p53 inhibitor PFT-␣. Thus, we define the BCL6 gene as a new p53 target, regulated through a RE frequently disrupted in BNHL. ( IntroductionThe BCL6 transcriptional repressor mediates survival, proliferation, and differentiation blockade of B cells during the germinal-center (GC) reaction and is implicated in the pathogenesis of B-cell non-Hodgkin lymphoma (BNHL). BCL6 was originally identified by virtue of its involvement in 3q27 chromosomal translocations associated with 2 types of BNHL: diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). 1-3 BCL6 is selectively expressed in high levels in mature B cells in the GC, in which they undergo Ig gene somatic hypermutation (SHM), class switch recombination (CSR), and affinity maturation-based selection. BCL6 is required for GC formation and T-cell-dependent antibody responses. 4 BCL6 was shown to suppress genes involved in lymphocyte activation, differentiation, cell-cycle arrest, and apoptosis. 5 The balance between BCL6 and BLIMP-1, another transcriptional repressor, determines when and whether B cells will further differentiate into plasma cells. Introducing BCL6 into plasma cells caused them to "dedifferentiate" toward a B-cell state. 6 There is growing evidence of BCL6's role in lymphomagenesis. [7][8][9][10] Recently, BCL6 was shown to directly suppress p53 gene expression in GC B cells. 11 TP53 (also called p53) is a key tumor-suppressor gene that is mutated or lost in approximately 50% of all human cancer cases worldwide. 12 Downstream targets or upstream regulators of p53, such as p14 ARF and MDM2, are altered in many tumors with intact TP53. p53 is activated in response to a variety of cellular and genotoxic stress conditions, leading to the induction of growth arrest, apoptosis, DNA repair, senescence, and differentiation. 13 Many studies have shown that p53 exerts its various functions mainly by regulating gene expression of its t...