The role of H3K79 methylation in IDH-mutant leukemia

H3K79 甲基化在 IDH 突变白血病中的作用

• 批准号: 9010300
• 负责人: KATHRIN M BERNT
• 金额: $ 41.65万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-16 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9010300
• 关键词: Acute Myelocytic Leukemia; Bone Marrow Cells; Brain Neoplasms; Cell-Free System; Cells; Cessation of life; Chromatin; Clinical Trials; DNA; Data; Enzyme Inhibition; Enzymes; Epigenetic Process; Exhibits; Exposure to; Gene Expression; Genes; Genetic; Goals; Growth; Histones; Human; Hypermethylation; In Vitro; Isocitrate Dehydrogenase; Knock-out; Link; Lysine; Malignant Neoplasms; Mediating; Methylation; Modeling; Modification; Mus; Mutation; Patients; Pharmaceutical Preparations; Property; Proteins; Role; Sampling; Solid; System; Therapeutic Intervention; alpha ketoglutarate; base; demethylation; histone demethylase; histone methylation; in vivo; inhibitor/antagonist; knock-down; leukemia; leukemogenesis; loss of function; member; mouse model; mutant; new therapeutic target; novel therapeutic intervention; novel therapeutics; overexpression; programs; response

Project Summary Mutant forms of isocitrate dehydrogenase (IDH) have been identified in 20% of AML. The goal of this project is to better understand the effects of mutant IDH on chromatin, and to develop novel therapies for IDH-mutant AML. Mutant forms of IDH1/2 gain a neomorphic function, producing 2-hydroxyglutarate (2HG) instead of the normal metabolite αKG. 2HG inhibition of TET2, which mediates DNA hydroxymethylation, is a major mechanism of transformation by mutant IDH. However, 2HG also inhibits JmjC domain containing histone demethylases. Whether inhibition of JmjC demethylases and altered histone methylation contributes to leukemogenesis is currently not known. This project investigates the role of histone 3 lysine 79 methylation (H3K79me) in mutant-IDH mediated leukemogenesis. H3K79 methylation is increased in response to expression of mutant IDH, or exogenous exposure to 2HG, suggesting the existence of an H3K79 demethylase that is inhibited by 2HG. H3K79 is methylated by DOT1L. A contribution of aberrant H3K79 methylation to IDH–mutant leukemogenesis is highly relevant as a pharmacologic inhibitor of DOT1L is currently in clinical trials. This project will investigate whether DOT1L is required in IDH-mediated leukemogenesis using a murine leukemia model (SA1) as well as detailed analysis of changes in chromatin and gene expression in patient samples (SA2). Finally, the project aims to identify a demethylase for H3K79 (SA3).

项目摘要 在20％的AML中已经鉴定出异位酸脱氢酶（IDH）的突变形式。目标 该项目是为了更好地了解突变体IDH对染色质的影响，并开发 IDH突变AML的新型疗法。 IDH1/2的突变形式获得了新形态功能， 产生2-羟基戊二酸（2HG）而不是正常的代谢产物αkg。 2HG抑制 TET2介导DNA羟基甲基化，是通过转化的主要机制 突变IDH。但是，2HG还抑制含有组蛋白脱甲基酶的JMJC结构域。无论 抑制JMJC去甲基酶并改变了Hisstone甲基化有助于 白血病发生目前尚不清楚。该项目研究了组蛋白3赖氨酸79的作用 突变体介导的白血病发生中的甲基化（H3K79ME）。 H3K79甲基化是 由于突变IDH的表达或外源性暴露于2Hg而增加，表明 2Hg抑制的H3K79脱甲基酶的存在。 H3K79被DOT1L甲基化。 异常H3K79甲基化对IDH-突变的白血病的贡献高度相关，因为 DOT1L的药物结肠抑制剂目前正在临床试验中。这个项目将调查 在IDH介导的白血病模型中是否需要DOT1L （SA1）以及患者染色质和基因表达变化的详细分析 样品（SA2）。最后，该项目旨在确定H3K79（SA3）的脱甲基酶。