Sequential Transcription Factor Targeting for Diffuse Large B-Cell Lymphomas

Abstract

Transcription factors play a central role in malignant transformation by activating or repressing waves of downstream target genes. Therapeutic targeting of transcription factors can reprogram cancer cells to lose their advantages in growth and survival. The BCL6 transcriptional repressor plays a central role in the pathogenesis of diffuse large B-cell lymphomas (DLBCL) and controls downstream checkpoints, including the p53 tumor suppressor gene. We report that a specific inhibitor of BCL6 called BPI can trigger a p53 response in DLBCL cells. This was partially due to induction of p53 activity and partially due to relief of direct repression by BCL6 of p53 target genes. BPI could thus induce a p53-like response even in the presence of mutant p53. Moreover, sequential BCL6 peptide inhibitors followed by p53 peptide or small-molecule activators provided a more powerful antilymphoma effect than either treatment alone by maximally restoring p53 target gene expression. Therefore, tandem targeting of the overlapping BCL6 and p53 transcriptional programs can correct aberrant survival pathways in DLBCL and might provide an effective therapeutic approach to lymphoma therapy. [Cancer Res 2008;68(9):3361-9]

BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy

“…Yet even though expressed, p53 function is attenuated in DLBCL cells. Along these lines, previous data indicate that RI-BPI can induce the functional activity of already expressed p53 in DLBCL cells, regardless of whether p53 was mutant or wild type (41). p53-activating peptides or small molecules accordingly enhanced the cell-killing activity of RI-BPI, while in contrast, dominant negative p53 or the p53 inhibitor pifithrin-α partially rescued DLBCL cells from RI-BPI (41).…”

“…Along these lines, previous data indicate that RI-BPI can induce the functional activity of already expressed p53 in DLBCL cells, regardless of whether p53 was mutant or wild type (41). p53-activating peptides or small molecules accordingly enhanced the cell-killing activity of RI-BPI, while in contrast, dominant negative p53 or the p53 inhibitor pifithrin-α partially rescued DLBCL cells from RI-BPI (41). Connecting these data together suggests a scenario whereby RI-BPI induced, p300-mediated acetylation of p53 plays a crucial role in inducing p53 function and mediating antilymphoma effects.…”

“…For example, p300 acetylation of p53 can increase its transcriptional and biological actions (37)(38)(39)(40). While p53 is also a BCL6 target gene, it has been shown that not only mutant but also wild-type p53 can be expressed in DLBCL along with BCL6 (41,42). Yet even though expressed, p53 function is attenuated in DLBCL cells.…”

Mechanisms of action of BCL6 during germinal center B cell development

“…A SMRT-based cell penetrating BCL6 peptide inhibitor (BPI), which is designed to dissociate the BCL6 BTB domain and its co-repressors [14], was able to induce expression of genes such as ATR, TP53 and CDKN1A involved in DNA damage and cell cycle checkpoints in primary GC B cells and DLBCL cells, but did not affect expression of BCL6 target genes involved in differentiation such as PRDM1 [48]. Consistent with this, BPI administration prevented GC formation in mice and induced cell cycle arrest and apoptosis in DLBCL cells [14,47]. These studies suggest that the BTB domain is especially required for cell survival and proliferation.…”

“…BCL6 appears to recruit distinct co-repressor complex to different subsets of targets (Figure 1) [47,48], suggesting that transcriptional programming by BCL6 may be finely compartmentalized through distinct domains. A SMRT-based cell penetrating BCL6 peptide inhibitor (BPI), which is designed to dissociate the BCL6 BTB domain and its co-repressors [14], was able to induce expression of genes such as ATR, TP53 and CDKN1A involved in DNA damage and cell cycle checkpoints in primary GC B cells and DLBCL cells, but did not affect expression of BCL6 target genes involved in differentiation such as PRDM1 [48].…”