Chemical Modulation of Chromatin Signaling in Lymphoid Malignancies

淋巴恶性肿瘤中染色质信号传导的化学调节

• 批准号: 8929198
• 负责人: Christopher J Ott
• 金额: $ 9.81万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-18 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8929198
• 关键词: Acute Lymphocytic Leukemia; Animal Model; Binding; Biochemical; Biological Assay; Biology; Bromodomain; Cell Line; Cell Proliferation; Cell model; Cells; Cellular Assay; Cellular biology; ChIP-seq; Chemicals; Chemistry; Chromatin; Chromatin Structure; Chromosomal Rearrangement; Clinical Research; DNA Modification Methylases; Dependence; Dependency; Development; Distal; Down-Regulation; Drug Targeting; Elements; Enhancers; Epigenetic Process; FDA approved; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Health; Hematologic Neoplasms; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Human; IL7R gene; In Vitro; Lead; Ligands; Lysine; MYC gene; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediating; Mentors; Modeling; Mus; Nature; Oncogenes; Oncogenic; Output; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Proteins; Proto-Oncogene Proteins c-myc; Reader; Regulatory Pathway; Research; Role; Seasons; Signal Transduction; System; Testing; Therapeutic; Translations; Up-Regulation; Xenograft Model; Xenograft procedure; base; cancer cell; cell growth; cell type; chromatin protein; combinatorial; epigenome; genome-wide; genome-wide analysis; high throughput screening; histone acetyltransferase; inhibitor/antagonist; insight; interest; leukemia; leukemogenesis; malignant phenotype; next generation; novel; promoter; screening; small molecule; tool; transcription factor

DESCRIPTION (provided by applicant): Genetic aberrations in lymphoid malignancies, including acute lymphoblastic leukemias (ALLs), often include chromosomal rearrangements that result in the dramatic upregulation or dysregulation of transcription factors and other chromatin-associating proteins. This results in altered chromatin states and transcriptional outputs that lead to increased cellular proliferation and other malignant phenotypes. While the activity of transcription factors is very difficult to inhibit directly with small molecule drugs, chromatin-associating transcription co- factors that bind to histones have recently been shown to be amenable to small molecule inhibition. We have discovered and developed chemical probes for a class of protein modules called bromodomains, which are principally involved in the recognition of acetylated lysines on histones. Using these chemical probes, we have established a rationale for targeting this class of proteins in ALL. Treatment of ALL cells with bromodomain inhibitors leads to a dramatic reduction in expression of specific ALL oncogenes, including the notoriously 'undruggable' oncogenic transcription factor MYC. Selective disruption of oncogene expression leads to a decrease in ALL cell proliferation both in vitro and in murine xenograft models. The studies proposed here aim to characterize the mechanism by which bromodomain inhibition selectively effects specific oncogene expression in ALL cells, and to use these insights to further exploit putative ALL cell dependencies on chromatin-associating factors. Ours studies show that loss of MYC expression is a direct result of inhibiting the bromodomain-containing protein BRD4 from the MYC gene locus, leading to the hypothesis that BRD4 is an ALL-dependency gene. However, as BRD4 is widely expressed in many cell types, it remains to be seen how its inhibition leads to potent anti-ALL effects. In Aim 1, we will perfor genome-wide studies of bromodomain protein displacement with chemical probes using ChIP-seq, particularly focusing on effects within promoter distal cis-regulatory control elements of the genome, or enhancers. In Aim 2 we will study bromodomain inhibition in combination with other chromatin-targeting small molecules in ALL cells, primarily focusing on compounds that target histone acetylation including histone deacetylase and acetyltransferase probes. We will model these potential therapeutic combinations in murine models of disseminated ALL. Aim 3 of this proposal seeks to expand the chemical toolbox of chromatin-targeting small molecules, specifically focusing on the bromodomain of the ATAD2 protein, a MYC co-activator that is highly expressed in ALL. We will use high- throughput compound screening and iterative medicinal chemistry employing a suite of optimized bromodomain-binding assay systems. To achieve these aims, I have assembled an excellent and seasoned advisory team, including Dr. James Bradner [Mentor, DFCI], an expert in chemical biology and hematologic malignancies; Dr. Thomas Look [Co-mentor, DFCI] an expert in leukemogenesis and animal models of ALL; and Dr. Richard Young [Co-mentor, MIT], an expert in chromatin biology and transcriptional networks.

描述（由申请人提供）：淋巴恶性肿瘤中的遗传像差，包括急性淋巴细胞性白血病（ALLS），通常包括染色体重排，导致转录因子的急剧上调或失调，以及其他染色质蛋白 - 共同交往蛋白。这导致染色质状态和转录输出改变，导致细胞增殖和其他恶性表型增加。尽管转录因子的活性很难直接用小分子药物抑制，但最近已证明与组蛋白结合的染色质缔合转录因子与小分子抑制作用。我们已经发现并开发了一种称为溴化局的蛋白质模块的化学探针，这些探针主要参与组蛋白上乙酰化赖氨酸的识别。使用这些化学探针，我们已经建立了一个靶向这类蛋白质的理由。用溴结构域抑制剂对所有细胞进行处理，导致特定所有癌基因的表达急剧降低，包括臭名昭著的“不良”致癌转录因子MYC。癌基因表达的选择性破坏会导致所有细胞增殖的体外和鼠异种移植模型的降低。这里提出的研究旨在表征溴结构域抑制在所有细胞中选择性影响特定的Oncogene表达的机制，并使用这些见解进一步利用所有细胞依赖性对染色质促进因子的依赖性。我们的研究表明，MYC表达的丧失是抑制MYC基因基因座中含溴脱域BRD4的直接结果，导致假设BRD4是一个全依赖性基因。但是，由于BRD4在许多细胞类型中广泛表达，因此其抑制作用如何导致有效的抗抗效应尚待观察。在AIM 1中，我们将使用ChIP-Seq进行化学探针的溴结构域蛋白质位移的全基因组的研究，尤其是侧重于启动子内部顺式调节元素中的效果 基因组或增强子。在AIM 2中，我们将研究所有细胞中其他染色质小分子的溴结构域抑制作用，主要集中于靶向组蛋白乙酰化的化合物，包括组蛋白脱乙酰基酶和乙酰基转移酶探针。我们将在分布所有的鼠模型中对这些潜在的治疗组合进行建模。该提案的目标3旨在扩展呈染色质小分子的化学工具箱，专门针对ATAD2蛋白的溴结构域，ATAD2蛋白（一种MYC共激活剂，总共表达了）。我们将使用一套优化的溴结构域结合测定系统，使用高吞吐物化合物筛选和迭代药物化学。为了实现这些目标，我组建了一个出色的经验丰富的咨询团队，包括詹姆斯·布拉德纳（James Bradner）博士[Mentor，DFCI]，他是化学生物学和血液学恶性肿瘤专家； Thomas Look博士[Co-entor，DFCI]是白血病和动物模型的专家；以及理查德·杨（Richard Young）博士[Co-Intor，MIT]，染色质生物学和转录网络专家。

项目成果

HDAC Inhibitors Finally Open Up: Chromatin Accessibility Signatures of CTCL.

HDAC 抑制剂最终开放：CTCL 的染色质可及性特征。

• DOI: 10.1016/j.ccell.2017.06.008
• 发表时间: 2017
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Ott,ChristopherJ;Wu,CatherineJ
• 通讯作者: Wu,CatherineJ