Hdac3 as a therapeutic target in BCL6-dependent lymphoma

描述(申请人提供)：B细胞淋巴瘤-6(BCL6)是一种转录抑制因子，招募HDAC3来抑制DNA损伤反应基因的转录，如ATM和ATR，这些基因向p53肿瘤抑制因子发出信号。在弥漫性大B细胞淋巴瘤(DLBCL)中，bcl6是染色体易位的靶点，它驱动高水平、持续的bcl6抑制P53功能，从而推动淋巴瘤的发展。作为介导BCL6功能的关键酶，HDAC3是治疗DLBCL和其他高表达BCL6的肿瘤(高达DLBCL的30%)的一个有吸引力的靶点。我们的初步数据表明，B细胞中HDAC3的缺失导致了与Bcl6失活时观察到的表型相似的表型。此外，依赖于bcl6的DLBCL细胞株对HDAC3选择性抑制剂敏感。因此，我们假设抑制HDAC3将预防或治愈由BCL6过表达驱动的B细胞淋巴瘤。这一假说将直接使用BCL6过度表达和B细胞特异性HDAC3缺失的小鼠模型进行验证。BCL6转基因小鼠是一种经过验证的DLBCL模型，它允许直接和明确地测试HDAC3在预防或治疗B细胞淋巴瘤中的作用。这项工作有很大的潜力迅速转化到临床上，因为FDA批准了针对HDAC3的组蛋白去乙酰酶抑制剂SAHA(Vorinostat)和Depsi多肽(Romidessin)。此外，许多公司正在开发HDAC3的抑制剂，我们将比较广谱HDAC抑制剂和一种针对HDAC3的新的异构体选择性抑制剂的作用。此外，通过了解HDAC3失活对B细胞发育和功能的影响，我们将揭示这一关键调控酶在染色质结构、基因表达以及B细胞发育过程中的V-D-J和类开关重组中的基本作用。最后，这项工作还将确定HDAC3在B细胞中长期失活的副作用。这一综合方法将最终确定HDAC3是否是B细胞淋巴瘤的治疗靶点，并可能刺激进一步的临床试验和/或进一步开发HDAC3的选择性抑制剂。

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.