Response of Eμ-Myc lymphomas of different genotypes to DNA-damaging drugs in vitro and in vivo
| . | Etoposide response in vitro* . | Cyclophosphamide response in vivo . | |||
|---|---|---|---|---|---|
| Pre-B lymphomas . | B-cell lymphomas . | ||||
| 200 mg/kg . | 300 mg/kg . | 200 mg/kg . | 300 mg/kg . | ||
| Noxa−/− | S | S | S | S | S |
| Puma−/− | M | M | S† | S | S |
| Noxa−/−Puma+/− | S | S | S | S | S |
| Noxa−/−Puma−/− | M | M | S† | S | S |
| Bim−/− | S | S | S | (M)‡ | S |
| p53−/− | R | R | R | R | R |
| . | Etoposide response in vitro* . | Cyclophosphamide response in vivo . | |||
|---|---|---|---|---|---|
| Pre-B lymphomas . | B-cell lymphomas . | ||||
| 200 mg/kg . | 300 mg/kg . | 200 mg/kg . | 300 mg/kg . | ||
| Noxa−/− | S | S | S | S | S |
| Puma−/− | M | M | S† | S | S |
| Noxa−/−Puma+/− | S | S | S | S | S |
| Noxa−/−Puma−/− | M | M | S† | S | S |
| Bim−/− | S | S | S | (M)‡ | S |
| p53−/− | R | R | R | R | R |
S indicates similar sensitivity to that seen for control (wild-type) Eμ-Myc lymphomas; M, midresistant, compared with control Eμ-Myc lymphomas; R, resistant, as seen for p53 loss. See Figures 2A-E, 3C-E, and supplemental Figure 3A-D.
Similar responses were observed in vitro for lymphoma cell lines of Pre-B and B-cell phenotype.
Significant resistance (P < .05 relative to control Eμ-Myc lymphomas) was observed with the loss of Puma; however, even with a concomitant loss of Noxa, this was not as severe as the resistance seen with the loss of p53. Pre-B lymphomas were more dependent on Puma, whereas B-cell lymphomas showed a trend toward dependence on Bim for optimal drug response (P < .08).
Relative to Eμ-Myc lymphomas lacking Puma, those lacking both Puma and Noxa were relatively more sensitive to CTX in vivo when treated with 300 mg/kg (see also Figure 2D; ordinal regression, P = .04).