Investigating novel synthetic lethal epigenetic interactions in Acute Myeloid Leukemia

研究急性髓系白血病的新型合成致死表观遗传相互作用

• 批准号: 10540411
• 负责人: JUNWEI SHI
• 金额: $ 36.95万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-13 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540411
• 关键词: 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine; Acetyltransferase; Acute Myelocytic Leukemia; Address; Arginine; Biological; Biological Assay; Bromodomain; CRISPR/Cas technology; Cancer cell line; Candidate Disease Gene; Cell Line; ChIP-seq; Chromatin; Chromosomal translocation; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Complement; Complementary DNA; Complex; Data; Dependence; Enhancers; Epigenetic Process; Essential Genes; Family; Genes; Genetic; Genetic Screening; Genetic Transcription; Genetically Engineered Mouse; Goals; Growth; Hematopoietic Neoplasms; Histones; Human Cell Line; In Vitro; Knock-out; Knowledge; Lead; Lysine; Maintenance; Malignant - descriptor; Malignant Neoplasms; Masks; Mediating; Methods; Modification; Molecular; Mouse Cell Line; Myeloid Cells; Myeloid Progenitor Cells; Oncogenic; Pathogenesis; Pathway interactions; Patients; Phenotype; Post-Translational Protein Processing; Proliferating; Proteins; RNA; Reader; Role; SMARCA4 gene; SWI/SNF Family Complex; Scanning; Stress; Therapeutic; Therapeutically Targetable; Transcription Coactivator; Transcription Regulation Pathway; Treatment Efficacy; acute myeloid leukemia cell; chromatin modification; chromatin remodeling; combinatorial; epigenetic regulation; histone acetyltransferase; improved; in vivo; inhibitor; innovation; insight; leukemia; molecular subtypes; mouse model; mutant; neoplastic cell; new therapeutic target; novel; overexpression; patient derived xenograft model; programs; protein complex; screening; self-renewal; therapeutic target; transcriptome sequencing; transcriptomics

Project Summary/Abstract Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by aberrant self-renewal and blocked differentiation of myeloid progenitor cells. Many of the oncogenic drivers of AML converge in dysregulation of epigenetic and transcriptional regulation pathways, generating de novo dependencies on these regulators. A handful of epigenetic dependencies have been identified in AML, however, single-agent inhibitors against epigenetic regulators have shown limited therapeutic efficacy in patients with AML. To improve our limited understanding of epigenetic-related synergistic genetic interactions in AML, we developed a highly efficient CRISPR-Cas12a-based method enabling us to perform double deletion genetic screening. Our preliminary studies identified and validated two pairs of novel interacting synthetic sick combinations of epigenetic regulators in AML: bromodomain containing protein 9 (BRD9) and Jumonji domain-containing protein 6 (JMJD6) as well as the lysine acetyltransferase 6 (KAT6) and JMJD6. JMJD6 is a bi-functional arginine demethylase and lysyl-hydroxylase regulating transcription enhancer activation and was identified in both synergistic pairs of epigenetic factor deletions. BRD9 is a component of chromatin remodeling SWI/SNF complex and was previously identified as an AML specific dependency. KAT6A is a histone acetyltransferase and transcriptional co-activator. We hypothesize that BRD9/JMJD6 and KAT6A/JMJD6 interact synergistically at the level of transcription and chromatin. The presence of JMJD6 in both interactions suggests that JMJD6- deficiency sets up a unique transcription and chromatin state that sensitizes AML cells to distinct epigenetic stresses. In Aim 1, we will investigate the synthetic sick interactions of BRD9/JMJD6 and KAT6A/JMJD6 in vitro and in vivo and in Aim 2, we will dissect the AML-specific synthetic sick interactions of BRD9/JMJD6 and KAT6A/JMJD6 at the molecular level. Our proposed studies will offer basic mechanistic insight into how these novel AML synthetic sick epigenetic interactions sustain AML pathogenesis. Successful completion of the proposed studies holds significant promise towards developing innovative epigenetic pathway-directed therapies and revealing fundamental biological insights into the pathogenesis of AML. 1

项目摘要/摘要 急性髓系白血病(AML)是一种血液系统恶性肿瘤，其特征是异常的自我更新和 抑制髓系祖细胞的分化。AML的许多致癌驱动因素汇聚在 表观遗传和转录调控通路的失调，产生从头开始的依赖 这些监管者。然而，在AML中已经发现了少数表观遗传依赖，然而，单一因素 针对表观遗传调节因子的抑制剂在AML患者中显示出有限的治疗效果。至 改善我们对AML中与表观遗传相关的协同遗传相互作用的有限理解，我们开发了 一种基于CRISPR-Cas12a的高效方法，使我们能够进行双缺失基因筛查。 我们的初步研究确定并验证了两对新的相互作用的合成病症组合 急性髓系白血病的表观遗传调节因子：含溴结构域蛋白9(BRD9)和含Jumonji结构域 蛋白6(JMJD6)以及赖氨酸乙酰转移酶6(KAT6)和JMJD6。JMJD6是一个双功能的 精氨酸脱甲基酶和赖氨酸羟基酶调节转录增强子激活，并在 两对协同作用的表观遗传因子缺失。BRD9是染色质重塑SWI/SNF的组成部分 复杂，以前被标识为AML特定依赖项。KAT6A是一种组蛋白乙酰转移酶 和转录共激活子。我们假设BRD9/JMJD6和KAT6A/JMJD6是协同作用的 在转录和染色质水平上。JMJD6在这两个相互作用中的存在表明JMJD6- 缺乏建立一种独特的转录和染色质状态，使AML细胞对不同的表观遗传敏感 压力。在目标1中，我们将研究BRD9/JMJD6和KAT6A/JMJD6在 在体外和体内，以及在目标2中，我们将剖析BRD9/JMJD6和JMJD6的AML特异性合成病态相互作用 KAT6A/JMJD6在分子水平上。我们提议的研究将提供基本的机械洞察，以了解这些 新的AML合成病症表观遗传相互作用支持AML的发病机制。圆满完成 拟议的研究对开发创新的表观遗传途径具有重大希望 治疗方法和揭示急性髓系白血病发病机制的基本生物学见解。 1