Loss of Puma and combined loss of Puma and Noxa promotes resistance to etoposide-induced apoptosis, but to a lesser extent than p53 deficiency. (A) Eμ-Myc cell lines of the indicated genotypes were treated with etoposide (0.2 μg/mL) for the indicated times in vitro, and cell death was assessed by flow cytometry. Apoptosis of Eμ-Myc/Puma^−/− cells was significantly lower than for control Eμ-Myc cells at 6 and 24 hours (P < .0001 and P < .05, respectively). Similar protection was observed for Eμ-Myc/Noxa^−/−Puma^−/− cells (P < .0001 and P < .001). ***P < .0001; **P < .001; *P < .05. Data represent mean ± SEM from 3-7 independent Eμ-Myc cell lines for each genotype, with each cell line analyzed in at least 3 independent experiments. (B-E) Response of primary Eμ-Myc lymphomas to CTX treatment in vivo: Kaplan-Meier survival curves of mice transplanted (day 0) with Eμ-Myc lymphomas and treated, once lymphomas became palpable, from around d12. Pre-B-cell (B) or B-cell (C) Eμ-Myc lymphomas of the relevant genotypes, including those lacking Noxa and/or Puma or p53, were treated with 200 mg/kg CTX. (D-E) Same as for (B-C), but treated with 300 mg/kg CTX. Data were pooled from 3-13 independent lymphomas (supplemental Table 1) of each of 7 genotypes and 2 immunophenotypes (total 276 independently derived lymphomas); 2-14 recipient mice per treatment per independent lymphoma.