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).

项目概要 已在 20% 的 AML 中发现了异柠檬酸脱氢酶 (IDH) 的突变形式。 该项目旨在更好地了解突变 IDH 对染色质的影响，并开发 IDH 突变 AML 的新疗法 IDH1/2 突变形式获得新形态功能， 产生 2-羟基戊二酸 (2HG)，而不是正常的代谢物 αKG 抑制。 TET2 介导 DNA 羟甲基化，是转化的主要机制 然而，2HG 也抑制含有组蛋白去甲基酶的 JmjC 结构域。 抑制 JmjC 去甲基化酶和改变组蛋白甲基化有助于 目前尚不清楚组蛋白 3 赖氨酸 79 的作用。 突变 IDH 介导的 H3K79 甲基化 (H3K79me) 是 响应突变 IDH 的表达或外源暴露于 2HG，表明 受 2HG 抑制的 H3K79 去甲基化酶的存在被 DOT1L 甲基化。 异常的 H3K79 甲基化对 IDH 突变型白血病的发生具有高度相关性，因为 DOT1L 的药物抑制剂目前正在进行临床试验，该项目将进行研究。 使用小鼠白血病模型研究 IDH 介导的白血病发生是否需要 DOT1L (SA1)以及患者染色质和基因表达变化的详细分析 最后，该项目旨在鉴定 H3K79 (SA3) 的去甲基化酶。