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

Oncogene volume 31, pages 3392–3396 (2012)Cite this article

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: BimBad 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, BimPuma, 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.

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Acknowledgements

We thank Mikara Robati and Owen Siggs for help with experiments; Jerry Adams, Suzanne Cory, Clare Scott and Cyril Clybouw for insightful discussions; and Eμ-Myc mice, Bruno Helbert and Carley Young for mouse genotyping; Emily Sutherland and Giovanni Siciliano for mouse husbandry; and Jason Corbin for blood sample analysis. This work was supported by the Australian National Health and Medical Research Council (program grant 461221, Australia Fellowship (AS) and Career Development Award (PB)), the National Cancer Institute (CA43540), the Australian Research Council (DM), the Leukemia and Lymphoma Society (LLS Specialized Center of Research grant 7015) and operational infrastructure grants through the Australian Government (IRISS) and the Victorian State Government (OIS).

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  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

    D Mérino, A Strasser & P Bouillet

  2. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia

    D Mérino, A Strasser & P Bouillet

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  1. D Mérino
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  2. A Strasser
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Correspondence to P Bouillet.

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Mérino, D., Strasser, A. & Bouillet, P. Bim must be able to engage all pro-survival Bcl-2 family members for efficient tumor suppression. Oncogene 31, 3392–3396 (2012). https://doi.org/10.1038/onc.2011.508

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