Hdac3 as a therapeutic target in BCL6-dependent lymphoma

描述（由申请人提供）：B细胞淋巴瘤-6 （BCL6）是一种转录抑制因子，它招募Hdac3来抑制DNA损伤反应基因（如ATM和ATR）的转录，这些基因向p53肿瘤抑制因子发出信号。BCL6是弥漫性大B细胞淋巴瘤（DLBCL）中染色体易位的靶点，这种易位驱动高、持续水平的BCL6抑制p53功能并驱动淋巴瘤的发展。作为介导BCL6功能的关键酶，Hdac3是DLBCL和其他过表达BCL6的癌症（高达30%的DLBCL）的一个有吸引力的治疗靶点。我们的初步数据表明，在B细胞中缺失Hdac3会导致类似于Bcl6失活时观察到的表型。此外，依赖BCL6的DLBCL细胞系对hdac3选择性抑制剂敏感。因此，我们假设抑制Hdac3可以预防或治愈由BCL6过表达驱动的B细胞淋巴瘤。这一假设将通过BCL6过表达与b细胞特异性缺失Hdac3的小鼠模型直接验证。BCL6转基因小鼠是一种被证实的DLBCL模型，它允许对Hdac3在预防或治疗B细胞淋巴瘤中的作用进行直接和明确的测试。由于FDA批准了组蛋白去乙酰化酶抑制剂SAHA （Vorinostat）和Depsipeptide （roidepsin）靶向Hdac3，因此这项工作具有快速转化为临床的巨大潜力。此外，许多公司正在开发Hdac3抑制剂，我们将比较广谱HDAC抑制剂与针对Hdac3的新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节酶在B细胞发育过程中染色质结构、基因表达、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B细胞中Hdac3长期失活的副作用。这种综合的方法将最终确定Hdac3是否是B细胞淋巴瘤的治疗靶点，并可能促进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.