Tumour suppressors such as ARF are multifunctional proteins that regulate a range of cell activities. But what then regulates the tumour suppressors? Pier Paolo Pandolfi and colleagues have shown that a transcription factor named Pokemon shuts down expression of ARF, and possibly other tumour-suppressor genes, to promote tumorigenesis.

Pokemon is a member of the POK family of DNA-binding proteins, which recruit histone deacetylases to promote chromatin remodelling. Pokemon has been previously shown to regulate differentiation of haematopoietic cells, and it physically interacts with BCL6, another haematopoietic cell transcription factor. Dysregulated BCL6 activity has been associated with lymphomagenesis. So the authors investigated whether alterations in Pokemon function might also impair cellular differentiation and lead to lymphoma.

They first observed that Pokemon-null fibroblasts were resistant to transformation by combinations of oncogenes that have tumorigenic effects in normal fibroblasts, such as activated HRAS , E1A or MYC . Conversely, fibroblasts that expressed transgenic Pokemon were resistant to apoptosis and senescence. Pokemon and BCL6 seemed to function together as oncogenes, as Pokemon expression was required for the immortalizing and transforming capabilities of BCL6 in fibroblasts.

As Pokemon is a transcription factor, Pandolfi's group set out to find its gene targets. ARF seemed like a logical candidate, because its inactivation promotes MYC and RAS-mediated transformation of cells. Indeed, they found several Pokemon-binding sites in the ARF promoter, and showed that Pokemon binding at this site was indispensable for repression of ARF transcription. Loss of ARF rescued the transformability of Pokemon-null cells, so ARF suppression seemed to be a key mechanism of Pokemon's oncogenic effect.

What happens in vivo? Transgenic mice that expressed Pokemon specifically in the immature T-cell and B-cell lineage developed aggressive T-cell lymphomas, and the authors observed that Pokemon is upregulated in a subset of human T-cell lymphomas. Furthermore, Pokemon was upregulated in diffuse large B-cell lymphoma and follicular lymphoma samples — two human tumour types that also express BCL6. Pandolfi and colleagues showed that lymphomas that expressed both Pokemon and BCL6 had a higher proliferative index than cells that only upregulated one of these factors, supporting the functional cooperation between these two transcription factors in promoting lymphomagenesis. Further studies could identify other Pokemon gene targets involved in tumorigenesis.