The fusion protein AML1/ETO (AE), resulting from the t(8;21) translocation, is a leukemia-initiating transcription factor that is frequently associated with acute myeloid leukemia (AML). Despite being defined as a ?favorable? subtype of AML, many AE positive (AE+) patients relapse and die with largely unknown causes. It is also unclear how AE mediates a disease-predictable DNA methylation signature. The long-term goals are to elucidate further the mechanisms of AE+ AML leukemogenesis, discover new therapeutic targets and develop effective targeted therapies. The objective of this proposal is to explore the molecular basis of a disease- predictable DNA methylation signature underlying AE+ AML with a focus on the impact of hypoxia-independent HIF1?-DNMT3a signaling axis activation. The rationale underlying this proposal is that the hypoxia- independent HIF1? signaling activation is a new hallmark of cancer. In relation to this project, the hyperactive HIF1? signaling may be a disease-promoting factor and an epigenetic mediator in AE+ AML. HIF1? forms a feedforward loop with AE and transactivates DNMT3a, another prognostic marker in AE+ AML. HIF1? inhibition suppresses AML cell growth. However, the detailed mechanistic and biochemical links between HIF1? signaling and AE AML pathogenesis and disease recurrence are poorly defined. The central hypothesis is that HIF1? promotes AE leukemogenicity through enhancing AE transcriptional activities and modulating the AE-governed DNA methylation landscape in AML cells; therefore HIF1? may be a vulnerable and druggable target in AE+ AML. This hypothesis will be tested by pursuing three specific aims: 1) Dissect the mechanistic details of how HIF1? is critical for AE-driven leukemogenesis; 2) Determine the role of HIF1? in AE-dependent DNA methylation; 3) Test pharmacological targeting of HIF1? as a therapeutic option for AE+ AML. To pursue our aims, we will use innovative combinations of biological techniques with unique transgenic and patient-derived xenograft (PDX) mouse models, as well as innovative integration of aberrant HIF1? signaling and epigenetics in understanding and treating AE+ AML. The proposed research is significant, because it will disclose new genes/mechanistic pathways that are necessary for AE leukemogenicity, identify the therapeutic biomarkers, and discover new medicinal agents for AE+ AML. Further, it will thoroughly investigate the epigenetic and oncogenic role of HIF1? in cancer. The proximate expected outcomes are to demonstrate HIF1?-epigenetics crosstalk in defining AE-initiated transcriptional regulation and leukemia pathogenesis, and to establish the feasibility of using HIF1? inhibitors to enhance the therapeutic index of the existing treatment regimens. The results will have an important impact because they will advance our understanding of AE+ AML molecular pathology, aberrant epigenetics in leukemia and the oncogenic functions of hypoxia-independent HIF1? signaling in cancers. The findings will also lay the groundwork to develop newer strategies to better target AE+ AML.
Leukemia patients harboring AML1/ETO fusion protein achieve complete remission initially, but many of them relapse and die. This project aims to understand the ways in which AML/ETO contributes to leukemogenesis. Findings will inform intervention strategies for leukemia therapy.
