A senescence rescue screen identifies <i>BCL6</i> as an inhibitor of anti-proliferative p19 ^ARF –p53 signaling

<jats:p> Senescence limits the proliferative capacity of primary cells in culture. We describe here a genetic screen to identify genes that allow bypass of this checkpoint. Using retroviral cDNA expression libraries, we identify <jats:italic>BCL6</jats:italic> as a potent inhibitor of senescence. <jats:italic>BCL6</jats:italic> is frequently activated in non-Hodgkin's lymphoma, but its mechanism of action has remained unclear. <jats:italic>BCL6</jats:italic> efficiently immortalizes primary mouse embryonic fibroblasts and cooperates with RAS in oncogenic transformation. <jats:italic>BCL6</jats:italic> overrides the senescence response downstream of p53 through a process that requires induction of <jats:italic>cyclin D1</jats:italic> expression, as <jats:italic>cyclin D1</jats:italic> knockout fibroblasts are specifically resistant to <jats:italic>BCL6</jats:italic> immortalization. We show that <jats:italic>BCL6</jats:italic> expression also dramatically extends the replicative lifespan of primary human B cells in culture and induces <jats:italic>cyclin D1</jats:italic> expression, indicating that <jats:italic>BCL6</jats:italic> has a similar activity in lymphoid cells. Our results suggest that <jats:italic>BCL6</jats:italic> contributes to oncogenesis by rendering cells unresponsive to antiproliferative signals from the p19 <jats:sup>ARF</jats:sup> –p53 pathway. </jats:p>