Acute myeloid leukemia (AML) is the most common adult leukemia in US. Although current chemotherapy is effective in inducing remission, most AML patients do relapse and the relapsed AML are more refractory to chemotherapy. Moreover, studies from several groups including one of us have identified genetic alterations that are associated with poor prognosis. Therefore, the major challenge in AML therapy is two-fold. The first is to reduce disease recurrence after remission is induced, while the second is to search effective therapy for those patients with recurrent AML or high-risk primary AML that responds poorly to existing therapy. Although it has been proposed that AML stem cells is a major underlying cause for AML recurrence and drug resistance, definitive evidence has yet to emerge to support the hypothesis, primarily because i) the current therapeutic approaches do not effectively eliminate AML stem cells and ii) the molecular and phenotypic characterization of AML SC is still evolving. In the past five years, we have used a spontaneous mouse lymphoma model and human AML samples to investigate the molecular programs responsible for maintenance of stem cells of hematological malignancies. Through these efforts, we have established an essential role for hypoxia-inducing factor 1 (HIF1 ) in the maintenance of the stem cells of both lymphoma and leukemia. In particular, we have demonstrated that Echinomycin, a drug well tolerated by human cancer patients, can selectively eliminate lymphoma and AML stem cells. Based on these exciting observations, we hypothesize that HIF1 activity is the converging point of the major CSC maintenance programs, including those programs controlled by Notch, mTOR, and Foxo3, and that HIF1 activity is also regulated by common genetic alterations in AML. Therefore, effective targeting of HIF may offer a novel approach for the treatment of both recurrent and drug-resistant AML. To test this hypothesis, we will establish the mTOR-HIF-FOXO-NOTCH program for AML maintenance, evaluate the impact of common recurrent AML mutations on HIF activity, and develop animal model for relapsed and genetically averse AML to test the therapeutic approach for AML stem cell elimination. Our proposed studies take advantage of the novel concept of HIF-mediated CSC maintenance, a state-of-the-art biospecimen- and clinical AML repository and the wealth of accumulated genetic information in our patient cohorts collected over the last 10 years. These studies will not only address the fundamental role served by CSC in AML recurrence, but also provide a highly translational and innovative approach to address the unmet medical challenges in contemporary AML therapy.