Similar to what was observed in retinoblastoma, we found that E2F1 and E2F3 contribute to increased malignancy associated with loss of Rb1. Since HELLS was identified as aE2F target gene and critical contributor of tumorigenesis in retinoblastoma, we evaluated the role of HELLS in osteosarcoma tumorigenesis. The gene discussed is HELLS; the disease is osteosarcoma.