p53 andINK4a/ARF mutations promote tumorogenesis and drug resistance, in part, by disabling apoptosis. We show that primary murine lympomas also respond to chemotherapy by engaging a senescence program controlled by p53 and p16^INK4a. Hence, tumors with p53 or INK4a/ARF mutations-but not those lacking ARF alone - respond poorly to cyclophosphamide therapy in vivo. Morover, tumors harboring a Bcl2-mediated apoptotic block undergo a drug-induced cytostasis involving the accumulation of p53, p16^INK4a, and senescence markers, and typically acquire p53 or INK4a mutations upon progression to a terminal stage. Finally, mice bearing tumors capable of drug-induced senescence have a much better prognosis following chemotherapy than those harboring tumors with senescence defects. Therefore, cellular senescence contributes to treatment outcome in vivo.

 Figure 1. Contribution of p53 and Bcl2 to Treatment Responses

Mice harboring ctrl.-MSCV, p53 null-MSCV, and ctrl.-bcl2 lymphomas were treated at comparable tumor burdens (day 0) with a single dose of cyclophosphamide (CTX) and monitored by whole-body fluorescence imaging. Representative examples are shown.