p53-dependent senescence delays Eμ-myc-induced B-cell lymphomagenesis

The effect of p53-dependent cell-cycle arrest and senescence on Eμ-myc-induced B-cell lymphoma development remains controversial. To address this question, we crossed Eμ-myc mice with the p53515C mutant mouse, encoding the mutant p53R172P protein that retains the ability to activate the cell-cycle inhibitor and senescence activator p21. Importantly, this mutant lacks the ability to activate p53-dependent apoptotic genes. Hence, Eμ-myc mice that harbor two p53515C alleles are completely defective for p53-dependent apoptosis. Both Eμ-myc::p53515C/515C and Eμ-myc::p53515C/+ mice survive significantly longer than Eμ-myc::p53+/– mice, indicating the importance of the p53-dependent non-apoptotic pathways in B-cell lymphomagenesis. In addition, the p53515C allele is deleted in several Eμ-myc::p53515C/+ lymphomas, further emphasizing the functionality of p53R172P in tumor inhibition. Lymphomas from both Eμ-myc::p53515C/515C and Eμ-myc::p53515C/+ mice retain the ability to upregulate p21, resulting in cellular senescence. Senescence-associated β-galactosidase (SA β-gal) activity was observed in lymphomas from Eμ-myc::p53+/+, Eμ-myc::p53515C/515C and Eμ-myc::p53515C /+ mice but not in lymphomas isolated from Eμ-myc::p53+/– mice. Thus, in the absence of p53-dependent apoptosis, the ability of p53R172P to induce senescence leads to a significant delay in B-cell lymphoma development.