The central goal of this project is to understand the role of BRD4 as a therapeutic target in acute myeloid leukemia. As a regulator of chromatin, BRD4 is a member of an emerging class of anti-cancer drug targets for which little is understood of its therapeutically-relevant molecular function. This proposal seeks to address this issue by identifying the critical biochemical mechanism employed by BRD4 in leukemia cells that accounts for its desirable properties as a therapeutic target. This will include evaluating which regions of BRD4 are most crucial for its disease-related functions, as well as identifying the key protein constituents of the BRD4 complex that are necessary for leukemia maintenance in experimental mouse models. Efforts will also be made to identify effective therapeutic combinations that can synergize with BRD4 inhibitors to suppress leukemia progression in preclinical leukemia models. This project will rely on integrative approaches, including biochemical, genetic, proteomic, and epigenomic strategies. This research will make extensive use of genetically-engineered mouse models of chemotherapy-resistant leukemia, which will be used to evaluate the in vivo efficacy of various therapeutic manipulations of BRD4 or components of its protein complex. In summary, the long-term goal of this research will be to maximize the clinical benefit of targeting BRD4 in leukemia through an understanding of the detailed mechanism of how this protein works as a regulator of chromatin state.
Our proposal will investigate the role of a novel drug target in human leukemia called BRD4, which we recently identified as an 'Achilles Heel'in this disease. Our studies will provide insights into how we can effectively exploit this vulnerability in leukemia as a therapeuti strategy.
|Xu, Yali; Vakoc, Christopher R (2017) Targeting Cancer Cells with BET Bromodomain Inhibitors. Cold Spring Harb Perspect Med 7:|
|Ipsaro, Jonathan J; Shen, Chen; Arai, Eri et al. (2017) Rapid generation of drug-resistance alleles at endogenous loci using CRISPR-Cas9 indel mutagenesis. PLoS One 12:e0172177|
|Hohmann, Anja F; Martin, Laetitia J; Minder, Jessica L et al. (2016) Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition. Nat Chem Biol 12:672-9|
|Tasdemir, Nilgun; Banito, Ana; Roe, Jae-Seok et al. (2016) BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance. Cancer Discov 6:612-29|
|Oran, Amanda R; Adams, Clare M; Zhang, Xiao-Yong et al. (2016) Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer. Oncotarget 7:72395-72414|
|Bhagwat, Anand S; Roe, Jae-Seok; Mok, Beverly Y L et al. (2016) BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements. Cell Rep 15:519-530|
|Martin, Laetitia J; Koegl, Manfred; Bader, Gerd et al. (2016) Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor. J Med Chem 59:4462-75|
|Zhang, Qiang; Zeng, Lei; Shen, Chen et al. (2016) Structural Mechanism of Transcriptional Regulator NSD3 Recognition by the ET Domain of BRD4. Structure 24:1201-8|
|Roe, Jae-Seok; Vakoc, Christopher R (2016) The Essential Transcriptional Function of BRD4 in Acute Myeloid Leukemia. Cold Spring Harb Symp Quant Biol 81:61-66|
|Somerville, Tim D D; Vakoc, Christopher R (2016) Modeling the Epigenetic Chain Reaction Downstream of DNMT3A(R882H). Cancer Cell 30:9-10|
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