Leukemia is a common blood cancer, with about 44,600 and 4,900 new cases expected to be diagnosed in the United States and Canada respectively in 2013. The introduction of Imatinib medication has improved treatment of chronic myeloid leukemia (CML), but early relapses and resistant disease prevent many patients from being cured. The frequency of resistance to current Imatinib therapy is 15-20%, increasing to 40% in patients with advanced phase disease. Research has now shown that this is due to the inability of current single drug treatment to eradicate the blood cancer stem cells, which maintain the potential for relapse. There is an urgent need to develop new combination therapies that also target other critical proteins active in CML blood cancer stem cells so that these critical cells can be effectively eliminated. One candidate target is AHI-1, a newly discovered cancer-causing gene (oncogene) we identified. AHI-1 is involved in blood cancer (leukemia) development and displays abnormal expression in CML blood cancer stem cells. Interestingly, we have recently found that AHI-1 plays a major role in abnormal blood cancer stem cell activity and resistance to Imatinib therapy in both mouse models and in blood cancer stem cells from CML patients, a strong indicator that AHI-1 is likely to be an important new cancer-causing gene involved in development of leukemia and drug resistance and that developing new drugs that inhibit its abnormal functions in blood cancer stem cells will be a more effective treatment option for CML patients. This proposal aims to develop new complementary therapies against other critical proteins, like AHI-1, that are involved in drug resistance, so that the blood cancer stem cells can be effectively eliminated. Our work will thus lead directly to the rationale design of new, complementary therapies that should produce more effective treatments in CML patients, particularly those will develop drug resistance to Imatinib therapy.