This observation could begin to explain why losses of neither E2f1 (p53/Rb1/E2f1 TKO) nor E2F3 (p53/Rb1/E3f3 TKO) were sufficient to reverse the increased malignancy observed upon Rb1 loss (p53/Rb1 DKO) in osteosarcoma but rather provided only partial improvements. Here, E2F1 is linked to osteosarcoma.