A model describing how loss of Bcl-xL prevents Εμ-myc–induced lymphoma development. (A) The combination of Myc-induced apoptosis and the absence of Bcl-xL pro-survival activity leads to a much smaller pool of pro-B and pre-B cells, the likely target cells for transformation, and the increased apoptosis at early stages of transformation balances Myc-induced proliferation, precluding tumor development. (B) The molecular basis of Myc-driven apoptosis. Myc overexpression up-regulates the BH3-only proteins Puma and Bim, in a p53-dependent manner for Puma and a p53-independent route for Bim.10,22-24 In bcl-x+/+ Myc-driven pre-leukemic cells, Bcl-xL and its pro-survival relatives (eg, Bcl-2) can sequester the up-regulated Puma and Bim, limiting the apoptosis. In the absence of Bcl-xL, however, the activated Bim and Puma overwhelm the remaining pro-survival proteins and (directly or indirectly) provoke activation of Bax and Bak. By balancing Myc-induced proliferation, the resulting apoptosis stops tumor formation.
