While critical insights into the pathogenesis of acute myeloid leukemia (AML) have come from studying its cytogenetics and genetics, and from modeling myeloid malignancies in mice, these advances have not translated into therapeutic gains. Our goal is to develop targeted therapies for AML driven by AML1-ETO (AE), a chimeric transcription factor (TF) with oncogenic properties that is generated by the most common chromosomal translocation found in AML, t(8;21). We discovered that the leukemogenicity of AE in mouse and human AML models and its ability to activate gene expression required both the binding of the p300 lysine acetyltransferase to AE, and its acetylation at lysine 43 (K43). Given the inherent difficulties of directly targeting a TF, we have explored ways of targeting AE required co- factors, and over the past four years have defined the efficacy of multiple p300/CBP inhibitors in AE+ AML, targeted protein-protein interactions vital for AE-driven oncogenesis (including TAF1) and defined several AE target genes critical for its leukemogenicity (such as ID1). As we continue this work, our hypothesis is that by studying interacting proteins, cooperating mutations, and downstream biological events, we will more fully understand the cellular machinery that drives AE-expressing (AE+) AML and more efficiently devise combinatorial therapeutic strategies against AML. To test this hypothesis, we have proposed the following specific aims: 1. Determine how AE-interacting proteins regulate its transcriptional regulatory and leukemogenic properties. a) Determine how TAF1 regulates the ability of AE to bind chromatin, alter gene expression, and promote HSC self-renewal and leukemogenesis using ChIP-seq and RNA-seq assays. b) Determine how other components of the AE-TAF1 complex (such as TAF7) impact its biological properties, and its activity at gene enhancers and promoters. 2. Determine how the absence of p300/ CBP, and the presence of epigenetic modifier mutations seen in AE+ AML, affects the transcriptional regulatory and leukemogenic properties of AE. a) Define the response of AE+ AML cells to loss of p300 or CBP, compared to chemical inhibition of p300/CBP by knocking out p300 or CBP in AE-driven leukemia mouse models b) Determine how mutations in ASXL1, ASXL2, and TET2 cooperate with AE to drive leukemogenesis by generating compound mice models and c) Determine how these mutations affect the response of AE+ AML to p300/CBP inhibition by treating AE+ mouse cells derived from these compound mice. 3. Develop combination epigenetic and signal transduction therapies that are effective against AE+ AML. a) Evaluate the efficacy of combination, epigenetic-targeted therapies, including inhibitors of p300/CBP and inhibitors of TAF1, on AE-driven AML cells. b) Evaluate the efficacy of combination therapies that target both the signal transduction pathways (e.g. inhibiting ID1/AKT signaling) and the epigenetic factors (p300, TAF1) that drive AE+ AML.
The AML1-ETO fusion transcription factor causes acute leukemia in humans, and we are studying the fundamental mechanisms that regulate its leukemia promoting ability. We are using biochemical approaches and mouse models to better understand the genesis of AML1-ETO driven leukemia and to devise new therapeutic strategies. By inhibiting its required co-factors, including the p300 and CBP enzymes, and impairing the protein-protein interactions vital for its function as an oncogene, we are developing more targeted approaches to this disease.
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