The recent introduction of Imatinib (IM) medication has dramatically improved the treatment of chronic myeloid leukemia (CML), but early relapses and the emergence of IM-resistant disease are an increasing problem. Growing evidence indicates that IM is not effective in eliminating leukemic stem cells, with disease returning after a period of apparent effect.  There is an urgent need to develop complementary therapies that target downstream proteins so that leukemic stem cells may be effectively attacked. This project will study the cooperating role of a newly-discovered cancer causing gene, AHI-1, as a potential therapeutic target for CML. AHI-1 is abnormally expressed in human leukemic stem cells from patients with CML. Furthermore, over-expression of the AHI-1 gene alone can cause leukemia in mouse models, with these effects being enhanced by the introduction of BCR-ABL, an oncogene that drives CML pathogenesis. Importantly, over-expression of AHI-1 in CML stem cells reduces their response to IM treatment.  These findings strongly indicate that AHI-1 is likely to be an important new cancer causing gene involved in the development of CML, and in mediation of CML stem cell response/resistance to IM. This study will explore how AHI-1 and its mutated forms interact with BCR-ABL to alter signalling pathways and to change stem cell behaviours that are involved in processes of disease and IM response/resistance.  These studies will identify specific target sites of AHI-1 that can be targeted for new molecular therapy in CML.