Hdac3 as a therapeutic target in BCL6-dependent lymphoma

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): 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.