BIM Is the Primary Mediator of MYC-Induced Apoptosis in Multiple Solid Tissues

MYC is one of the most frequently overexpressed oncogenes in human cancer, and even modestly deregulated MYC can initiate ectopic proliferation in many postmitotic cell types in vivo. Sensitization of cells to apoptosis limits MYC’s oncogenic potential. However, the mechanism through which MYC induces apoptosis is controversial. Some studies implicate p19ARF-mediated stabilization of p53, followed by induction of proapoptotic BH3 proteins NOXA and PUMA, whereas others argue for direct regulation of BH3 proteins, especially BIM. Here, we use a single experimental system to systematically evaluate the roles of p19ARF and BIM during MYC-induced apoptosis, in vitro, in vivo, and in combination with a widely used chemotherapeutic, doxorubicin. We find a common specific requirement for BIM during MYC-induced apoptosis in multiple settings, which does not extend to the p53-responsive BH3 family member PUMA, and find no evidence of a role for p19ARF during MYC-induced apoptosis in the tissues examined. [Display omitted] •MYC-induced apoptosis in multiple solid tissues requires BIM, but not ARF•BIM is a direct and specific transcriptional target of MYC•Induction of BIM mediates MYC sensitization to chemotherapy Muthalagu et al. now demonstrate a specific role for the BH3-only protein BIM in mediating MYC-induced apoptosis in multiple solid tissues and show that MYC-dependent sensitization to chemotherapy is likewise BIM dependent. The authors show that MYC-induced apoptosis requires neither p19ARF nor PUMA, upstream and downstream, respectively, of p53. The results suggest that BH3 mimetics may have broad therapeutic potential against solid tumors, even in the absence of functional p53.