The ARF-Mdm2-p53 tumor suppressor pathway is disrupted in Myc-induced lymphomagenesis. Transgenic mice expressing c-Myc under the control of the immunoglobulin heavy chain enhancer develop B-cell lymphomas with a mean survival time of about 6 months. The prolonged latency before disease onset is attributed to p53-dependent apoptosis that initially protects against tumor formation but is disabled when malignant cells emerge. In cultured primary mouse embryo fibroblasts, c-Myc activates the ARF-Mdm2-p53 pathway, enhancing p53-dependent apoptosis but selecting for cells with p53 mutations or biallelic ARF deletions. The study shows that p53 and ARF also potentiate Myc-induced apoptosis in primary pre-B-cell cultures, and that the ARF-Mdm2-p53 pathway is frequently inactivated in tumors from Eμ-myc transgenic mice. Many of these tumors sustain p53 or ARF loss of function, while others show elevated Mdm2 levels. ARF hemizygous mice develop accelerated disease, and 80% of these tumors lose the wild-type ARF allele. ARF-null mice die of lymphoma within weeks of birth. Many tumors from ARF hemizygous or nullizygous mice also overexpress Mdm2. These findings suggest that Myc activation strongly selects for spontaneous inactivation of the ARF-Mdm2-p53 pathway in vivo, canceling its protective function and accelerating malignancy. The study highlights the role of ARF and p53 in Myc-induced apoptosis and the importance of their loss in lymphomagenesis. The results indicate that ARF loss accelerates Myc-induced lymphomagenesis, and that Mdm2 overexpression may contribute to disease progression. The study also suggests that other genes may act in concert with ARF, p53, and Mdm2 in Myc-induced B-cell neoplasia.The ARF-Mdm2-p53 tumor suppressor pathway is disrupted in Myc-induced lymphomagenesis. Transgenic mice expressing c-Myc under the control of the immunoglobulin heavy chain enhancer develop B-cell lymphomas with a mean survival time of about 6 months. The prolonged latency before disease onset is attributed to p53-dependent apoptosis that initially protects against tumor formation but is disabled when malignant cells emerge. In cultured primary mouse embryo fibroblasts, c-Myc activates the ARF-Mdm2-p53 pathway, enhancing p53-dependent apoptosis but selecting for cells with p53 mutations or biallelic ARF deletions. The study shows that p53 and ARF also potentiate Myc-induced apoptosis in primary pre-B-cell cultures, and that the ARF-Mdm2-p53 pathway is frequently inactivated in tumors from Eμ-myc transgenic mice. Many of these tumors sustain p53 or ARF loss of function, while others show elevated Mdm2 levels. ARF hemizygous mice develop accelerated disease, and 80% of these tumors lose the wild-type ARF allele. ARF-null mice die of lymphoma within weeks of birth. Many tumors from ARF hemizygous or nullizygous mice also overexpress Mdm2. These findings suggest that Myc activation strongly selects for spontaneous inactivation of the ARF-Mdm2-p53 pathway in vivo, canceling its protective function and accelerating malignancy. The study highlights the role of ARF and p53 in Myc-induced apoptosis and the importance of their loss in lymphomagenesis. The results indicate that ARF loss accelerates Myc-induced lymphomagenesis, and that Mdm2 overexpression may contribute to disease progression. The study also suggests that other genes may act in concert with ARF, p53, and Mdm2 in Myc-induced B-cell neoplasia.