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 (BCL6) 是一种转录抑制因子，它招募 Hdac3 来抑制 DNA 损伤反应基因（例如向 p53 肿瘤抑制因子发出信号的 ATM 和 ATR）的转录。 BCL6 是弥漫性大 B 细胞淋巴瘤 (DLBCL) 中染色体易位的靶标，它会驱动 BCL6 持续高水平，从而抑制 p53 功能并推动淋巴瘤的发展。作为介导 BCL6 功能的关键酶，Hdac3 是 DLBCL 和其他过度表达 BCL6 的癌症（高达 30% 的 DLBCL）的有吸引力的治疗靶点。我们的初步数据表明，B 细胞中 Hdac3 的缺失会导致与 Bcl6 失活后观察到的表型相似的表型。此外，依赖于 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 将预防或治愈 BCL6 过表达驱动的 B 细胞淋巴瘤。该假设将使用 BCL6 过度表达以及 B 细胞特异性 Hdac3 缺失的小鼠模型进行直接测试。 BCL6 转基因小鼠是经过验证的 DLBCL 模型，可以直接、明确地测试 Hdac3 在预防或治疗 B 细胞淋巴瘤中的作用。这项工作具有快速转化为临床的巨大潜力，因为 FDA 批准了针对 Hdac3 的组蛋白脱乙酰酶抑制剂 SAHA（Vorinostat）和 Depsipeptide（Romidepsin）。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 的新型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，我们将揭示这种关键调节酶在 B 细胞发育过程中染色质结构、基因表达以及 V-D-J 和类别转换重组中的基本作用。最后，这项工作还将明确 B 细胞中 Hdac3 长期失活的副作用。这种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 选择性抑制剂。 公共健康相关性：BCL6 招募组蛋白脱乙酰酶 3 (Hdac3) 来抑制转录并引发 B 细胞淋巴瘤。该应用将确定 Hdac3 失活是否可以预防或治愈由 BCL6 过度表达引起的 B 细胞淋巴瘤。