Epigenetic Mechanisms Underpinning Mantle Cell Lymphoma Sensitivity and Resistance to Notch Inhibitors

表观遗传机制支持套细胞淋巴瘤对Notch抑制剂的敏感性和耐药性

• 批准号: 10445457
• 负责人: Robert Babak Faryabi
• 金额: $ 42.08万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445457
• 关键词: 3-Dimensional; Address; B-Cell Antigen Receptor; B-Cell Lymphomas; B-Cell Neoplasm; Binding; Biological Assay; Biopsy; Bypass; Cells; Chromatin; Chromatin Loop; Chronic Lymphocytic Leukemia; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cytokine Signaling; DNA; Data; Disease Progression; Dominant-Negative Mutation; Drug resistance; Elements; Enhancers; Epigenetic Process; Event; FYN gene; Frequencies; GTP-Binding Protein alpha Subunits, Gs; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genetic Enhancer Element; Genetic Transcription; Genome; Genome engineering; Genomics; Goals; Growth; Histones; Homeostasis; Image; Individual; Instruction; Insulator Elements; Kinetics; Knowledge; LYN gene; Lymphoma cell; Malignant Neoplasms; Mantle Cell Lymphoma; Mediating; Mutate; Mutation; Nuclear; Oncogenic; Optics; Outcome; Pathway interactions; Patients; Positioning Attribute; Prognosis; Proteins; Receptor Signaling; Reporting; Resistance; Resolution; Role; SP1 gene; Sampling; Signal Pathway; Signal Transduction; Testing; Therapeutic; Work; Zinc Fingers; addiction; base; chemotherapy; chromosome conformation capture; functional genomics; gain of function; gamma secretase; genome editing; improved; inhibitor; notch protein; programs; promoter; protein expression; receptor; targeted treatment; transcription factor; tumor growth; tumorigenesis

Project Summary Gain-of-function Notch mutations are among the most frequent mutations in small B cell lymphomas, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Harboring Notch mutation is also a predictor of poor outcomes in small B cell lymphomas, which despite recent advances remain incurable with chemotherapy. Together, these observations provide a compelling rationale for focusing on Notch inhibitors as potential therapeutic options in small B cell lymphomas. Unfortunately, progress in treating patients with Notch inhibitors has been stymied partly due to a limited understanding of underlying mechanisms of sensitivity and resistance to Notch inhibitors. Here, we represent a concerted effort to overcome these limitations and fill major gaps in current knowledge by testing our central hypothesis that Notch-driven activation and positioning of enhancers synergize Notch and several crucial signaling pathways to co-activate pro-growth and survival genes in small B cell lymphomas. This premise is based on our preliminary data showing an important consequence of Notch inhibition is decommissioning and repositioning of putative enhancer elements associated with key genes in primary small B cell lymphoma samples, including several components of B cell receptor (BCR) and cytokine signaling pathways. We will test this hypothesis by using cutting-edge functional genomics, chromatin conformation capture, genome engineering, and single-cell resolution genomics and optical assays. We will systematically determine: i) the Notch-dependent enhancer activation and nuclear positioning, and their genomic requirements that together mediate crosstalk between Notch, BCR and cytokine signaling pathways; ii) the rewiring of Notch-driven epigenetic program that enables drug-resistant cells to bypass effects of Notch inhibitors and maintain the expression of critical Notch targets. Together, these complementary studies will greatly expand understanding of epigenetic mechanisms underpinning sensitivity and resistance to Notch inhibitors and provide a clearer rationale for targeting Notch in small B cell lymphoma.

项目摘要 功能收益凹槽突变是小B细胞淋巴瘤中最常见的突变之一，包括 慢性淋巴细胞白血病（CLL）和地幔细胞淋巴瘤（MCL）。藏有Notch突变也是 小型B细胞淋巴瘤中不良预后的预测指标，尽管最近进展仍然无法治愈 化学疗法。这些观察结果共同为专注于Notch抑制剂作为一个令人信服的理由 小B细胞淋巴瘤中的潜在治疗选择。不幸的是，治疗Notch患者的进展 抑制剂的部分原因是，由于对敏感性的潜在机制的理解有限 对缺口抑制剂的抗性。在这里，我们代表着一致克服这些限制并充满专业的努力 通过测试我们的核心假设，即置于Notch驱动的激活和定位，从而在当前知识中的差距 增强剂协同凹口和几个关键信号通路，以共同激活促生长基因和生存基因 在小B细胞淋巴瘤中。此前提是基于我们的初步数据，显示了 Notch抑制是退役和重新定位与关键基因相关的推定增强子元件 在主要的小B细胞淋巴瘤样品中，包括B细胞受体（BCR）和细胞因子的几个成分 信号通路。我们将通过使用尖端功能基因组学，染色质检验该假设 构象捕获，基因组工程和单细胞分辨率基因组学和光学测定。我们将 系统地确定：i）Notch依赖性增强子的激活和核定位及其基因组 要求共同介导Notch，BCR和细胞因子信号通路之间的串扰； ii） 重新启动Notch驱动的表观遗传程序，使耐药细胞绕过Notch抑制剂的影响 并保持关键缺口目标的表达。这些互补研究将大大扩展 了解表观遗传机制的敏感性和对缺口抑制剂的抗性的理解，并提供 靶向小B细胞淋巴瘤中缺口的更明显的理由。