Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis

The ARF and p53 tumor suppressors mediate Myc-induced apoptosis and suppres s lymphoma development in E mu -myc transgenic mice. Here we report that th e proapoptotic Bcl-2 family member Bax also mediates apoptosis triggered by Myc and inhibits Myc-induced lymphomagenesis. Bax-deficient primary pre-B cells are resistant to the apoptotic effects of Myc, and Bax loss accelerat es lymphoma development in E mu -myc transgenics in a dose-dependent fashio n. Eighty percent of lymphomas arising in wild-type E mu -myc transgenics h ave alterations in the ARF-Mdm2-p53 tumor suppressor pathway characterized by deletions in ARF, mutations or deletions of p53, and overexpression of M dm2. The absence of Bax did not alter the frequency of biallelic deletion o f ARF in lymphomas arising in E mu -myc transgenic mice or the rate of tumo rigenesis in ARF-null mice. Furthermore, Mdm2 was overexpressed at the same frequency in lymphomas irrespective of Bax status, suggesting that Bax res ides in a pathway separate from ARF and Mdm2. Strikingly, lymphomas from Ba x-null E mu -myc transgenics lacked p53 alterations, whereas 27% of the tum ors in Bax(+/-) E mu -myc transgenic mice contained p53 mutations or deleti ons. Thus, the loss of Bax eliminates the selection of p53 mutations and de letions, but not ARF deletions or Mdm2 overexpression, during Myc-induced t umorigenesis, formally demonstrating that Myc-induced apoptotic signals thr ough ARF/Mdm2 and p53 must bifurcate: p53 signals through Bax, whereas this is not necessarily the case for ARF and Mdm2.