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.