Hdac3 as a therapeutic target in BCL6-dependent lymphoma

Hdac3 作为 BCL6 依赖性淋巴瘤的治疗靶点

基本信息

批准号：
8607465
负责人：
SCOTT W HIEBERT
金额：
$ 39.1万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
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/8607465
关键词：
Adverse effects Affect Antibodies Antibody Affinity B-Cell Development B-Cell Lymphomas B-Lymphocytes BCL6 gene 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&apos s lymphoma leukemia/lymphoma mouse model novel prevent programs promoter response small molecule therapeutic target tumor

项目摘要

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.

描述（由申请人提供）：B细胞淋巴瘤-6（BCl6）是转录阻遏物，它募集HDAC3抑制DNA损伤反应基因的转录，例如ATM和ATR，该基因（例如ATM和ATR）向P53肿瘤抑制器发出信号。 Bcl6是弥漫性大B细胞淋巴瘤（DLBCL）中染色体易位的靶标，该染色体驱动高，连续的BCl6水平以抑制p53功能并驱动淋巴瘤发育。作为介导BCl6功能的关键酶，HDAC3是DLBCLS和其他超过Bcl6（DLBCL的30％）的吸引人的治疗靶标。我们的初步数据表明，B细胞中HDAC3的缺失会导致与Bcl6失活时相似的表型。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将预防或治愈由Bcl6过度表达驱动的B细胞淋巴瘤。该假设将使用BCL6过表达的小鼠模型与HDAC3的B细胞特异性缺失结合使用。 Bcl6转基因小鼠是DLBCL的验证模型，可以直接且明确测试HDAC3在预防或固化B细胞淋巴瘤中的作用。由于FDA批准的组蛋白脱乙酰基酶抑制剂SAHA（Vorinostat）和Depsipeptide（Romidepsin）靶靶HDAC3，这项工作具有迅速转化为诊所的巨大潜力。此外，许多公司都在开发HDAC3的抑制剂，我们将将广谱HDAC抑制剂的作用与针对HDAC3的新型同工型选择性抑制剂进行比较。同样，通过了解HDAC3失活对B细胞发育和功能的影响，我们将发现该关键调节酶在染色质结构，基因表达以及V-D-J和类开关在B细胞发育过程中的基本作用。最后，这项工作还将定义B细胞中HDAC3长期失活的副作用。这种全面的方法将最终定义HDAC3是否是B细胞淋巴瘤中的治疗靶点，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。