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.
| Tarumoto, Yusuke; Lu, Bin; Somerville, Tim D D et al. (2018) LKB1, Salt-Inducible Kinases, and MEF2C Are Linked Dependencies in Acute Myeloid Leukemia. Mol Cell 69:1017-1027.e6 |
| Xu, Yali; Milazzo, Joseph P; Somerville, Tim D D et al. (2018) A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia. Cancer Cell 33:13-28.e8 |
| Somerville, Tim D D; Xu, Yali; Miyabayashi, Koji et al. (2018) TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal Adenocarcinoma. Cell Rep 25:1741-1755.e7 |
| Huang, Yu-Han; Klingbeil, Olaf; He, Xue-Yan et al. (2018) POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Genes Dev 32:915-928 |
| Bhagwat, Anand S; Lu, Bin; Vakoc, Christopher R (2018) Enhancer dysfunction in leukemia. Blood 131:1795-1804 |
| Skucha, Anna; Ebner, Jessica; Schmöllerl, Johannes et al. (2018) MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity. Nat Commun 9:1983 |
| Fontanals-Cirera, Barbara; Hasson, Dan; Vardabasso, Chiara et al. (2017) Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene. Mol Cell 68:731-744.e9 |
| 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 |
| 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 |
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