Hdac3 as a therapeutic target in BCL6-dependent lymphoma

Hdac3 作为 BCL6 依赖性淋巴瘤的治疗靶点

• 批准号: 8230922
• 负责人: SCOTT W HIEBERT
• 金额: $ 40.45万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-20 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230922
• 关键词: Adverse effects; Affect; Antibodies; Antibody Affinity; B-Cell Development; B-Cell Lymphomas; B-Lymphocytes; Cell Line; Cell physiology; Chromatin Structure; Chromosomal translocation; Clinic; Clinical Trials; Complement; Complex; Cutaneous; DNA Damage; DNA Double Strand Break; Data; Depsipeptides; Development; Enzymes; FDA approved; Gene Expression; Genes; Genetic; Genetic Transcription; Growth; HDAC3 gene; Hand; Histone Deacetylase Inhibitor; Hormones; Human; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Immunoglobulin Variable Region; In Vitro; Knowledge; Lymphoma; Malignant Neoplasms; Mediating; Modeling; Molecular; Mutation; Nuclear; Oncogene Proteins; Oncogenes; Pathway interactions; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Protein Isoforms; Protein p53; Recruitment Activity; Repression; Role; S Phase; Signal Pathway; Signal Transduction; Staging; Structure of germinal center of lymph node; T-Cell Lymphoma; Testing; Therapeutic; Transcription Repressor/Corepressor; Transgenic Mice; Translating; V(D)J Recombination; Vorinostat; Work; base; cancer cell; cancer therapy; efficacy testing; histone deacetylase 3; inhibitor/antagonist; killings; large cell Diffuse non-Hodgkin' s lymphoma; leukemia/lymphoma; mouse model; novel; prevent; programs; promoter; response; small molecule; therapeutic target; tumor

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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：B细胞淋巴瘤-6（BCL 6）是一种转录抑制因子，其募集Hdac 3以抑制DNA损伤反应基因（如向p53肿瘤抑制因子发出信号的ATM和ATR）的转录。BCL 6是弥漫性大B细胞淋巴瘤（DLBCL）中染色体易位的靶标，其驱动高、连续水平的BCL 6以抑制p53功能并驱动淋巴瘤发展。作为介导BCL 6功能的关键酶，Hdac 3是DLBCL和过表达BCL 6（高达DLBCL的30%）的其他癌症中有吸引力的治疗靶点。我们的初步数据表明，在B细胞中Hdac 3的缺失导致与Bcl 6失活后观察到的表型相似的表型。此外，依赖于BCL 6的DLBCL细胞系对Hdac 3选择性抑制剂敏感。因此，我们假设Hdac 3的抑制将预防或治愈由BCL 6过表达驱动的B细胞淋巴瘤。将使用BCL 6过表达结合Hdac 3的B细胞特异性缺失的小鼠模型直接测试该假设。BCL 6转基因小鼠是DLBCL的经证实的模型，其允许直接且明确地测试Hdac 3在预防或治愈B细胞淋巴瘤中的作用。这项工作具有很大的潜力，可以迅速转化为临床，因为FDA批准的组蛋白脱乙酰酶抑制剂SAHA（伏立诺他）和Depsipeptide（罗米地辛）靶向Hdac 3。此外，许多公司正在开发Hdac 3的抑制剂，我们将比较广谱HDAC抑制剂与靶向Hdac 3的新亚型选择性抑制剂的作用。此外，通过了解Hdac 3失活对B细胞发育和功能的影响，我们将揭示这种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和类别转换重组中的基本作用。最后，这项工作还将确定长期灭活B细胞中的Hdac 3的副作用。这种综合方法将最终确定Hdac 3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Hdac 3选择性抑制剂的进一步开发。 公共卫生相关性：BCL 6招募组蛋白脱乙酰酶3（Hdac 3）抑制转录并触发B细胞淋巴瘤。本申请将确定Hdac 3的失活是否可以预防或治愈由BCL 6过表达驱动的B细胞淋巴瘤。