Cellular consequences of the loss of PHF6 function in leukemia cells. Functional loss of the epigenetic regulator PHF6 affects the balance between DNA replication and DNA repair in difficult-to-replicate DNA heterochromatin regions, with subsequent destabilization of common fragile sites and genomic instability. To survive, PHF6-deficient tumor cells must develop adaptive mechanisms and this provides a platform for therapeutic targeting. Professional illustration by Patrick Lane, ScEYEnce Studios.