Bim must be able to engage all pro-survival Bcl-2 family members for efficient tumor suppression

Abstract

Overexpression of the transcriptional regulator Myc is thought to be the cause or a contributing factor in the development of a large number of human lymphomas and certain other cancers. Apoptotic cell death constitutes a tumor suppressive mechanism, particularly in the context of Myc overexpression. Accordingly, lymphoma development in Eμ-Myc transgenic mice, which mimic the Myc/IgH chromosomal translocation that causes Burkitt lymphoma, is accelerated by concomitant overexpression of anti-apoptotic Bcl-2 family members or loss of pro-apoptotic BH3-only proteins, such as Bim. Bim binds with high affinity to all pro-survival Bcl-2-like proteins and can also interact with Bax/Bak, but it remains unclear which of these interactions are critical for its tumor suppressive function. We have previously generated knock-in mutant mice in which the BH3 region of Bim has been exchanged with that for Bad, Noxa or Puma so that it can only bind to select pro-survival Bcl-2-like proteins: Bim Bad binding to Bcl-2, Bcl-xL and Bcl-w, but not Mcl-1 or A1; BimNoxa binding only to Mcl-1 and A1 and as a control, Bim Puma, which can still bind all pro-survival Bcl-2-like proteins. We have now inter-crossed these Bim mutant mice with Eμ-Myc transgenic mice, and found that both the BimBad and the BimNoxa mutations but not the BimPuma mutation greatly accelerate Myc-induced lymphoma development and increase leukemic burden. These results demonstrate that for optimal tumor suppressive activity, Bim must be able to interact with all and not just select pro-survival Bcl-2 family members. © 2012 Macmillan Publishers Limited All rights reserved.