Germinal-centre-derived B-cell lymphomas are commonly associated with chromosome translocations or mutations that activate expression of BCL6 , which encodes a transcriptional repressor. Very few BCL6 target genes have been identified, however, so it has been unclear how its dysregulation might lead to cancer. In Nature, Ryan Phan and Riccardo Dalla-Favera report that BCL6 suppresses the expression of p53 to block DNA-damage-induced apoptosis in developing B cells.

In a survey of genes that rise and fall depending on levels of BCL6 expression, Phan and Dalla-Favera noticed that many were also targets of p53. This prompted them to investigate whether BCL6 might directly repress p53. This seemed reasonable as p53 is not expressed in cells that express high levels of BCL6, such as germinal-centre B cells. They showed that the p53 promoter did indeed contain a sequence that bound BCL6 protein, leading to downregulation of gene expression. Furthermore, inhibition of BCL6 with short interfering RNA in cultured B cells resulted in a 2–3-fold increase in p53 expression.

How might BCL6-mediated downregulation of p53 lead to lymphoma? The authors showed that treatment of cultured B cells with the DNA-damaging agent etoposide normally led to BCL6 downregulation and a resulting increase in p53 expression. B-cell lines engineered to constitutively express BCL6, as cancer cells do, could not upregulate p53, and were therefore resistant to etoposide-induced apoptosis.

In the normal B-cell lineage, BCL6 is highly expressed only in mature B cells within the germinal centre — the structure where immunoglobin genes undergo genomic rearrangements such as somatic hypermutation and class-switch recombination. Phan and Dalla-Favera propose that in normal germinal-centre B cells, BCL6 upregulation suppresses p53-mediated responses as these cells undergo genome remodelling events required for B-cell development. BCL6 is normally then downregulated in response to large amounts of DNA damage, such as that induced by etoposide. The constitutive activation of this gene through mutation or chromosome translocation, however, causes p53-mediated responses to be permanently suppressed, leading to lymphomagenesis. These findings indicate that some types of lymphoma might be treated with reagents that target BCL6 and induce p53.