The study investigates the disruption of the ARF–Mdm2–p53 tumor suppressor pathway in Myc-induced lymphomagenesis. In primary mouse embryo fibroblasts, c-Myc activates the ARF–Mdm2–p53 pathway, enhancing p53-dependent apoptosis. In primary pre-B-cell cultures, p53 and ARF also potentiate Myc-induced apoptosis. In Ep–myc transgenic mice, spontaneous inactivation of the ARF–Mdm2–p53 pathway occurs frequently in tumors, with many tumors sustaining either p53 loss or ARF deletion. ARF deletion accelerates lymphomagenesis, and Mdm2 overexpression is observed in some tumors lacking p53 function. The findings suggest that the ARF–Mdm2–p53 pathway plays a crucial role in preventing Myc-induced lymphomagenesis, and that disruption of this pathway can lead to accelerated tumor progression.The study investigates the disruption of the ARF–Mdm2–p53 tumor suppressor pathway in Myc-induced lymphomagenesis. In primary mouse embryo fibroblasts, c-Myc activates the ARF–Mdm2–p53 pathway, enhancing p53-dependent apoptosis. In primary pre-B-cell cultures, p53 and ARF also potentiate Myc-induced apoptosis. In Ep–myc transgenic mice, spontaneous inactivation of the ARF–Mdm2–p53 pathway occurs frequently in tumors, with many tumors sustaining either p53 loss or ARF deletion. ARF deletion accelerates lymphomagenesis, and Mdm2 overexpression is observed in some tumors lacking p53 function. The findings suggest that the ARF–Mdm2–p53 pathway plays a crucial role in preventing Myc-induced lymphomagenesis, and that disruption of this pathway can lead to accelerated tumor progression.