Bcl-2 family
It had been widely thought that all oncogenic changes enhance cell proliferation. This view was overturned in 1988 when we showed that bcl-2, the gene activated by the t14;18 translocation in follicular lymphoma, promotes cell survival rather than proliferation (Vaux, Cory and Adams Nature 1988). Further, we found that myc and bcl-2 were highly synergistic in driving leukemogenesis (Strasser et al Nature 1990), due to Bcl-2 countering the apoptosis driven by Myc when cytokines become limiting. Recently, we found that Bcl-2-promoted development of follicular lymphoma requires a proliferative stimulus provided by T-cell help (Egle et al Blood 2004). The concept that disturbances to programs controlling cell survival and proliferation are both essential steps in oncogenesis is now widely accepted.
In collaboration with other laboratories in the Molecular Genetics of Cancer Division, we are currently exploiting mouse genetics to explore how opposing factions of the Bcl-2 family of proteins control apoptosis, particularly during haemopoiesis; how mutations affecting this life/death switch can contribute to the development of malignancies; and how different family members influence the cytotoxic responses to chemotherapy and radiation. Key findings include the following:
- The Bcl-2 antagonist ABT-737 developed by Abbott Laboratories targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized (van Delft et al Cancer Cell 2006 PMID: 17097561)
- The BH3 mimetic ABT-737 can be highly efficacious in treating aggressive Myc-driven lymphomas, especially in combination therapy (Mason, Vandenberg et al PNAS 2008 PMID: 19004807)
- The BH3-only proteins Puma and, to a lesser extent, Noxa, are suppressors of Myc-induced lymphomagenesis (Michalak et al Cell Death Differentiation 2009 PMID: 19148184)
- Apoptosis of human tumour cell lines harbouring a mutant B-RAF that is induced with a MEK inhibitor requires the BH3-only protein Bim and is enhanced by the BH3-mimetic ABT-737 (Cragg et al J Clin Invest 2008 PMID: 18949058)
- Pan-haemopoietic expression of Mcl-1, a relative of Bcl-2, confers resistance to diverse cytotoxic signals and promotes lymphoma development (Campbell et al Blood 2010, Epub ahead of print)