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 #
5R01CA174793-02
Application #
8635318
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mufson, R Allan
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$532,576
Indirect Cost
$250,790
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
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
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 15:519-30
Shen, Chen; Ipsaro, Jonathan J; Shi, Junwei et al. (2015) NSD3-Short Is an Adaptor Protein that Couples BRD4 to the CHD8 Chromatin Remodeler. Mol Cell 60:847-59
Roe, Jae-Seok; Mercan, Fatih; Rivera, Keith et al. (2015) BET Bromodomain Inhibition Suppresses the Function of Hematopoietic Transcription Factors in Acute Myeloid Leukemia. Mol Cell 58:1028-39
Shen, Chen; Vakoc, Christopher R (2015) Gain-of-function mutation of chromatin regulators as a tumorigenic mechanism and an opportunity for therapeutic intervention. Curr Opin Oncol 27:57-63
Matthews, Geoffrey M; Mehdipour, Parinaz; Cluse, Leonie A et al. (2015) Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies. Blood 126:2392-403
Shi, Junwei; Wang, Eric; Milazzo, Joseph P et al. (2015) Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains. Nat Biotechnol 33:661-7
Bhagwat, Anand S; Vakoc, Christopher R (2015) Targeting Transcription Factors in Cancer. Trends Cancer 1:53-65
Wang, Eric; Kawaoka, Shinpei; Roe, Jae-Seok et al. (2015) The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer. Elife 4:e06377
(2014) Cancer therapy resistance: chasing epigenetics. Nat Med 20:340-1

Showing the most recent 10 out of 14 publications