A rare, uniformly lethal, undifferentiated midline carcinoma of young people is defined by the t(15;19)(p13.1;q13), whose product is the BRD4-NUT1 fusion oncogene. The molecular mechanism of BRD4-NUT1 carcinomas (BNCs) is unusual for a carcinoma, but resembles leukemias and sarcomas. Study of leukemic fusion oncogenes has provided important insights into oncogenic pathways, and normal hematopoietic development. These insights have led to the development of rational molecular therapies. The predicted BRD4-NUT1 fusion protein contains two BRD4-derived bromodomains, which bind acetylated histones in regions of transcriptionally active chromatin, and two NUT1-derived transcriptional activation domains. We have found that withdrawal of BRD4-NUT1 from BNC cell lines results in striking changes in vitro and in vivo that are consistent with the induction of squamous differentiation, suggesting that BRD4- NUT1 contributes to carcinogenesis by blocking terminal epithelial differentiation. These observations have led us to formulate two hypotheses, which serve to organize the studies proposed in this application: 1. BRD4-NUT1 blocks differentiation by altering the transcription of critical regulator(s) of epithelial cell differentiation. 2. This alteration in transcription is enacted by the interaction of NUT1 with specific protein partners. An underlying subtext is that these studies are likely to elucidate pathways that are vital to epithelial cell differentiation, proliferation, and neoplasia. In doing so, it is hoped that new rational therapeutic strategies relevant to BNCs and possibly other epithelial tumors will emerge. Based on these preliminary data and hypotheses, we propose the following three specific aims: 1. To identify the domains of BRD4-NUT1 that are necessary and sufficient to block differentiation. 2. To identify the BRD4-NUT1-interacting proteins that execute the downstream events that lead to the blockade of differentiation. 3. To identify the transcriptional targets of BRD4-NUT1 that are responsible for the blockade of differentiation in BRD4-NUT1 carcinoma cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA124633-04
Application #
7840409
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Mietz, Judy
Project Start
2007-08-30
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$299,250
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Alekseyenko, Artyom A; Walsh, Erica M; Zee, Barry M et al. (2017) Ectopic protein interactions within BRD4-chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma. Proc Natl Acad Sci U S A 114:E4184-E4192
Hellquist, Henrik; French, Christopher A; Bishop, Justin A et al. (2017) NUT midline carcinoma of the larynx: an international series and review of the literature. Histopathology 70:861-868
Chau, Nicole G; Hurwitz, Shelley; Mitchell, Chelsey M et al. (2016) Intensive treatment and survival outcomes in NUT midline carcinoma of the head and neck. Cancer 122:3632-3640
Stathis, Anastasios; Zucca, Emanuele; Bekradda, Mohamed et al. (2016) Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628. Cancer Discov 6:492-500
Sholl, Lynette M; Nishino, Mizuki; Pokharel, Saraswati et al. (2015) Primary Pulmonary NUT Midline Carcinoma: Clinical, Radiographic, and Pathologic Characterizations. J Thorac Oncol 10:951-9
Alekseyenko, Artyom A; Walsh, Erica M; Wang, Xin et al. (2015) The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains. Genes Dev 29:1507-23
French, Christopher A; Rahman, Shaila; Walsh, Erica M et al. (2014) NSD3-NUT fusion oncoprotein in NUT midline carcinoma: implications for a novel oncogenic mechanism. Cancer Discov 4:928-41
Puliyel, Mammen M; Mascarenhas, Leo; Zhou, Shengmei et al. (2014) Nuclear protein in testis midline carcinoma misdiagnosed as adamantinoma. J Clin Oncol 32:e57-60
Grayson, Adlai R; Walsh, Erica M; Cameron, Michael J et al. (2014) MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma. Oncogene 33:1736-1742
French, Christopher A (2013) The importance of diagnosing NUT midline carcinoma. Head Neck Pathol 7:11-6

Showing the most recent 10 out of 20 publications