Myeloid leukaemias display a diverse range of chromosome abnormalities. Chromosome translocations involving the MLL gene, which encodes an H3K4 methyl transferase, account for 5-6% of acute myeloid leukaemias (AMLs). The most common MLL translocation that causes AML in children and adults is the fusion with the gene AF9.
AML is often associated with high levels of Mcl-1, an anti-apoptotic member member of the Bcl-2 family. We are using a retroviral approach to study the impact of overexpression of Mcl-2 and Bcl-2 on the development and treatment of MLL-AF9- induced AML. An MLL-AF9 retrovirus was used to infect fetal liver cells from wild-type, VavP-Mcl-1 and VavP-BCL-2 transgenic mice and these cells were then used to reconstitute haemopoiesis in lethally irradiated mice to determine the impact of overexpression of the antiapoptotic proteins on tumour latency and phenotype. In vitro studies are in progress to determine sensitivity to drugs currently used in the clinic to treat AML, and to test whether combination therapy with a BH3 mimetic is likely to enhance drug efficacy.