Suppression of apoptosis is central to the evolution of cancer and the BCL2 family of pro- and anti-apoptotic genes is a key mediator in this process. BIM is a pro-apoptotic family member and a crucial antagonist of BCL2 survival function. As BCL2 is an oncoprotein, BIM might well be a tumour suppressor — in theory, loss of BIM function is equal to a gain in BCL2 function.
Suzanne Cory and colleagues now show that this is the case in the mouse B-lymphocyte lineage; but, unexpectedly, Bim acts as a tumour suppressor only in mature B cells. The authors investigated how disruption of the Bim gene affected tumour development in lymphoma-prone, B-cell-targeted (Eμ)-Myc mice. Loss of Bim – even one allele – markedly accelerated tumour onset and all the early neoplasms were acute leukaemias of surface IgM-positive B cells. By contrast, earlier results from this lab had demonstrated that the combination of transgenic Bcl2 and Myc in the same system induces lymphomas derived from immature lympho-myeloid progenitor cells.
Pertinently, before tumour onset, Bim loss changed the composition of the B-lymphoid compartment. Eμ-Myc transgenic mice have far more B-lymphoid cells than wild-type animals and pre-B cells predominate. By contrast, mature B cells hold sway in Eμ-Myc Bim-deficient animals. The authors speculate that the preferential increase in B cells is indicative of a crucial role for Bim in mediating Myc-induced apoptosis in mature B-cells. In the pre-B cells, Bim might be less influential because Myc also activates other pro-apoptotic proteins.
Why do Myc and Bim cooperate in B-cell leukaemia development? The authors found that Bim protein levels were increased in cells expressing the Eμ-Myc transgene, especially in mature B cells, and that inactivation of even one Bim allele protected the cells against apoptosis. They conclude that Bim mediates Myc-induced apoptosis in B-lymphoid cells, although no evidence was found that Bim is a direct transcriptional target of Myc.
Previously, this group demonstrated that the loss of one allele of Bim could correct many of the tissue defects within Bcl2-null animals, establishing Bim as a key physiological antagonist of Bcl2. Their most recent data, however, clearly show that the oncogenic impact of loss of Bim in the B-lymphoid compartment is not equivalent to gain of Bcl2. Unraveling this conundrum in the future will undoubtedly tell us more about the sophisticated circuitry regulating cell life and death during B-lymphoid differentiation.
References
ORIGINAL RESEARCH PAPER
Egle, A. et al. Bim is a suppressor of Myc-induced mouse B-cell leukemia. PNAS 101, 6164–6169 (2004)
FURTHER READING
Strasser, A. et al. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348, 331–333 (1990)
Cory, S. & Adams, J. The Bcl2 family: regulators of the cellular life-or-death switch. Nature Rev. Cancer 2, 647–656 (2002)
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McCarthy, N. Profit and loss. Nat Rev Cancer 4, 420 (2004). https://doi.org/10.1038/nrc1375
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DOI: https://doi.org/10.1038/nrc1375