B cell lymphoma-6 (BCL6) is a transcriptional repressor that recruits Hdac3 to repress the transcription of DNA damage response genes such as ATM and ATR that signal to the p53 tumor suppressor. BCL6 is the target of chromosomal translocations in diffuse large B cell lymphoma (DLBCL), which drive high, continuous, levels of BCL6 to suppress p53 functions and drive lymphoma development. As a key enzyme that mediates BCL6 functions, Hdac3 is an attractive therapeutic target in the DLBCLs and other cancers that over express BCL6 (up to 30% of DLBCL). Our preliminary data suggests that deletion of Hdac3 in B cells causes a phenotype similar to that observed upon inactivation of Bcl6. Moreover, DLBCL cell lines that are dependent on BCL6 were sensitive to Hdac3-selective inhibitors. As such, we hypothesize that inhibition of Hdac3 will prevent or cure B cell lymphoma driven by BCL6 over- expression. This hypothesis will be directly tested using a mouse model of over-expression of BCL6 in conjunction with B-cell-specific deletion of Hdac3. The BCL6 transgenic mouse is a proven model of DLBCL that allows a direct and unambiguous test of the role of Hdac3 in preventing or curing B cell lymphoma. This work has great potential to be rapidly translated to the clinic as the FDA approved histone deacetylase inhibitors SAHA (Vorinostat) and Depsipeptide (Romidepsin) target Hdac3. In addition, many companies are developing inhibitors of Hdac3 and we will compare the action of broad-spectrum HDAC inhibitors with a new isoform selective inhibitor that targets Hdac3. Also, by understanding the effects of inactivation of Hdac3 on B cell development and functions, we will uncover the fundamental roles of this key regulatory enzyme in chromatin structure, gene expression, and V-D-J and class switch recombination during B cell development. Finally, this work will also define the side effects of long-term inactivation of Hdac3 in B cells. This comprehensive approach will conclusively define whether Hdac3 is a therapeutic target in B cell lymphoma and may spur further clinical trials and/or further development of selective inhibitors of Hdac3.
BCL6 recruits Histone Deacetylase 3 (Hdac3) to repress transcription and trigger B cell lymphoma. This application will determine if inactivation of Hdac3 can prevent or cure B cell lymphoma that is driven by BCL6 over expression.
|Jiang, Yanwen; Ortega-Molina, Ana; Geng, Huimin et al. (2017) CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas. Cancer Discov 7:38-53|
|Cho, Sung Hoon; Raybuck, Ariel L; Stengel, Kristy et al. (2016) Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature 537:234-238|
|Zhao, Yue; Liu, Qi; Acharya, Pankaj et al. (2016) High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML. Cell Rep 16:2003-16|
|Stengel, Kristy R; Hiebert, Scott W (2015) Class I HDACs Affect DNA Replication, Repair, and Chromatin Structure: Implications for Cancer Therapy. Antioxid Redox Signal 23:51-65|
|Wang, Liqing; Liu, Yujie; Han, Rongxiang et al. (2015) FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3. J Clin Invest 125:1111-23|
|Stengel, Kristy R; Zhao, Yue; Klus, Nicholas J et al. (2015) Histone Deacetylase 3 Is Required for Efficient T Cell Development. Mol Cell Biol 35:3854-65|
|Ha, Kyungsoo; Fiskus, Warren; Choi, Dong Soon et al. (2014) Histone deacetylase inhibitor treatment induces 'BRCAness' and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells. Oncotarget 5:5637-50|
|Summers, Alyssa R; Fischer, Melissa A; Stengel, Kristy R et al. (2013) HDAC3 is essential for DNA replication in hematopoietic progenitor cells. J Clin Invest 123:3112-23|
|Thapa, Puspa; Das, Joy; McWilliams, Douglas et al. (2013) The transcriptional repressor NKAP is required for the development of iNKT cells. Nat Commun 4:1582|
|Ziesché, Elisabeth; Kettner-Buhrow, Daniela; Weber, Axel et al. (2013) The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-?B. Nucleic Acids Res 41:90-109|
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