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: 10580845
• 负责人: Robert Babak Faryabi
• 金额: $ 40.89万
• 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/10580845
• 关键词: 3-Dimensional; Ablation; 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; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genetic Enhancer Element; Genetic Transcription; Genome; Genome engineering; Genomics; Goals; Growth; Histones; Homeostasis; Image; Individual; 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; Proliferating; Proteins; Receptor Signaling; Reporting; Resistance; Resolution; Role; SH2B gene; SP1 gene; Sampling; Signal Pathway; Signal Transduction; Testing; Therapeutic; Work; Zinc Fingers; addiction; chemotherapy; chromosome conformation capture; functional genomics; gain of function; genome editing; improved; inhibitor; notch protein; programs; promoter; protein expression; receptor; secretase; synergism; 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.

项目总结