Establishing that Hdac3 is a therapeutic target in a subset of B cell Lymphoma

确定 Hdac3 是 B 细胞淋巴瘤亚型的治疗靶点

• 批准号: 9924498
• 负责人: SCOTT W HIEBERT
• 金额: $ 39.06万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924498
• 关键词: Accounting; Acetylation; Affect; Antigens; B-Cell Development; B-Cell Lymphomas; B-Lymphocyte Subsets; B-Lymphocytes; BCL6 gene; Binding; CREBBP gene; Cell Line; Cell Survival; Cells; ChIP-seq; Chromatin Structure; Clinic; Cutaneous T-cell lymphoma; DNA; DNA Binding; DNA Binding Domain; DNA biosynthesis; DNA replication fork; Data; Deposition; Development; Diagnosis; Enhancers; Enzymes; FOXO1A gene; Gap Junctions; Gene Activation; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Goals; HDAC1 gene; HDAC3 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone H3; Histone H4; Histones; Impairment; In Vitro; Inositol; Lead; Light; Lymphoma; Lymphoma cell; Lymphomagenesis; Lysine; Malignant Neoplasms; Maps; Mature B-Lymphocyte; Mediating; Metabolism; Methods; Multiple Myeloma; Mus; Mutation; N-terminal; NADH; Non-Hodgkin' s Lymphoma; Nucleosomes; Oncogenes; Patients; Pharmaceutical Preparations; Phenotype; Play; Proto-Oncogene Proteins c-akt; Reaction; Recurrence; Regulation; Repression; Resistance; Signal Transduction; Sirtuins; Structure; Structure of germinal center of lymph node; Testing; Therapeutic; Toxic effect; Transcription Coactivator; Transcriptional Regulation; V(D)J Recombination; Work; chemotherapy; gene repression; in vivo; inhibitor/antagonist; inositol 4-phosphate; large cell Diffuse non-Hodgkin' s lymphoma; mutant; recruit; response; sensor; success; targeted treatment; therapeutic target

Histone deacetylase 3 (HDAC3) deacetylates selective lysine residues on histone H3 and H4 to control chromatin structure and repress gene expression. During murine B cell development, Hdac3 is required for efficient V-D-J recombination, but once past this developmental stage B cells lacking Hdac3 survive, but fail to undergo a productive germinal center reaction in response to antigen. Rather, these cells accumulate in the “light zone” of the germinal center where the phenotype and gene expression pattern of Hdac3-/- B cells matched those of Foxo1-/- B cells. This is remarkable because Foxo1 recruits Hdac3. While Foxo1 is typically thought of as a transcriptional activator, in germinal center B cells, genes identified in ChIP-seq studies as bound by Foxo1 were up-regulated when Foxo1 was deleted. Moreover, in 10% of the lymphoma derived from the germinal center Foxo1 is activated by mutations that allow it to escape negative regulation by Akt. The convergence between Foxo1 and Hdac3, suggested that Hdac3 might play a key role in Foxo1-dependent diffuse large B cell lymphoma (DLBCL). Treatment of 8 different DLBCL cell lines with a selective Hdac3 inhibitor showed that only the cells with activating mutations in Foxo1 were sensitive, whereas cells containing other common mutations such as translocation of BCL6 were not. Moreover, this inhibitor caused activation of genes that were bound by Foxo1 in ChIP-exo studies. These preliminary studies lead to the hypothesis that Hdac3 is a viable therapeutic target in Foxo1 mutant diffuse large B cell lymphoma. This hypothesis will be directly tested by creating mice containing B cell lymphoma driven by mutant Foxo1 and then deleting Hdac3. In addition, we will fine map the domain in Foxo1 required for recruitment of Hdac3 and make mutants that cannot bind to Hdac3 to test whether recruitment of Hdac3 is required for lymphomagenesis and lymphoma cell survival. We will also use cutting-edge genomic methods such as PRO-seq to define the mechanism by which Hdac3 recruitment by Foxo1 regulates gene expression. This comprehensive approach will conclusively define whether Hdac3 is a therapeutic target in B cell lymphoma and may spur further development of selective inhibitors of Hdac3 and/or Foxo1.

组蛋白脱乙酰基酶3（HDAC 3）使组蛋白H3和H4上的选择性赖氨酸残基脱乙酰基以控制 染色质结构和抑制基因表达。在鼠B细胞发育过程中，Hdac 3是 有效的V-D-J重组，但一旦经过这个发育阶段，缺乏Hdac 3的B细胞存活，但 不能对抗原进行有效的生发中心反应。相反，这些细胞积累 Hdac 3-/- B的表型和基因表达模式 细胞与Foxo 1-/- B细胞匹配。这是值得注意的，因为Foxo 1招募了Hdac 3。Foxo 1是 通常被认为是转录激活因子，在生殖中心B细胞中，ChIP-seq中鉴定的基因 当Foxo 1缺失时，与Foxo 1结合的研究被上调。此外，在10%的 来源于生发中心Foxo 1的淋巴瘤被允许其逃逸的突变激活 Akt的负调节作用。Foxo 1和Hdac 3之间的收敛表明Hdac 3可能起作用， 在Foxo 1依赖性弥漫性大B细胞淋巴瘤（DLBCL）中起关键作用。8种不同DLBCL细胞的处理 具有选择性Hdac 3抑制剂的细胞系显示，只有Foxo 1中具有激活突变的细胞才能被激活。 敏感，而含有其他常见突变（如BCL 6易位）的细胞则不敏感。 此外，这种抑制剂导致在ChIP-exo研究中被Foxo 1结合的基因的激活。这些 初步的研究提出了这样的假设，即Hdac 3是Foxo 1突变型弥漫性神经胶质瘤中可行的治疗靶点。 大B细胞淋巴瘤。这一假设将通过建立含有B细胞淋巴瘤的小鼠来直接检验 由突变体Foxo 1驱动，然后删除Hdac 3。此外，我们将精细映射Foxo 1中的域 并制备不能与Hdac 3结合的突变体，以测试Hdac 3的募集是否 Hdac 3的表达是淋巴瘤发生和淋巴瘤细胞存活所必需的。我们还将使用最先进的 基因组方法，如PRO-seq，以确定Foxo 1募集Hdac 3的机制， 调节基因表达。这种综合方法将最终确定Hdac 3是否是一种 B细胞淋巴瘤的治疗靶点，并可能刺激Hdac 3选择性抑制剂的进一步开发 和/或Foxo 1。