The role of H3K79 methylation in IDH-mutant leukemia

项目摘要 已在20%的AML中鉴定出异柠檬酸脱氢酶（IDH）的突变形式。的目标 该项目旨在更好地了解突变IDH对染色质的影响，并开发 IDH突变型AML的新疗法。IDH 1/2的突变形式获得了一个新的函数， 产生2-羟基戊二酸（2 HG）而不是正常代谢产物αKG。2 HG抑制 TET 2介导DNA羟甲基化，是通过DNA甲基化转化的主要机制。 IDH突变体然而，2 HG也抑制含有JmjC结构域的组蛋白去甲基化酶。是否 抑制JmjC去甲基化酶和改变的组蛋白甲基化有助于 白血病发生目前尚不清楚。本项目研究组蛋白3赖氨酸79的作用 甲基化（H3 K79 me）在muplant-IDH介导的白血病发生中的作用。H3 K79甲基化是 响应于突变IDH的表达或外源性暴露于2 HG而增加，表明 H3 K79去甲基化酶的存在被2 HG抑制。H3 K79被DOT 1 L甲基化。 异常H3 K79甲基化对IDH突变型白血病发生的贡献是高度相关的， DOT 1 L的药理学抑制剂目前处于临床试验中。本项目将调查 使用小鼠白血病模型确定DOT 1 L是否在IDH介导的白血病发生中是必需的 (SA1)以及详细分析患者中染色质和基因表达的变化， 样品（SA 2）。最后，该项目旨在确定H3 K79（SA 3）的脱甲基酶。

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).