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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA174793-01
Application #
8478858
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mufson, R Allan
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$549,047
Indirect Cost
$258,546
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
Shi, Junwei; Vakoc, Christopher R (2014) The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell 54:728-36
(2014) Cancer therapy resistance: chasing epigenetics. Nat Med 20:340-1
Xu, Yali; Vakoc, Christopher R (2014) Brd4 is on the move during inflammation. Trends Cell Biol 24:615-6
Bhagwat, Anand S; Vakoc, Christopher R (2014) A new bump in the epigenetic landscape. Mol Cell 53:857-8