The role of H3K79 methylation in IDH-mutant leukemia

项目摘要 在20%的AML中发现了异柠檬酸脱氢酶(IDH)的突变形式。的目标是 这个项目是为了更好地了解突变的idh对染色质的影响，并开发 IDH突变型急性髓系白血病的新疗法。IDH1/2的突变形式获得新的功能， 产生2-羟基戊二酸(2HG)，而不是正常代谢产物αKG。2HG抑制 TET2，介导DNA羟甲基化，是转化的主要机制，通过 突变型IDH。然而，2HG也抑制含有组蛋白去甲基酶的JmjC结构域。是否 抑制JmjC去甲基酶和改变组蛋白甲基化有助于 白血病的发生目前尚不清楚。本项目研究了组蛋白3赖氨酸79的作用。 突变-IDH介导的白血病发生中的甲基化(H3K79me)。H3K79甲基化是 对突变型IDH的表达或外源暴露2HG的反应增加，表明 存在被2HG抑制的H3K79去甲基酶。H3K79由DOT1L甲基化。 异常的H3K79甲基化与IDH突变白血病的发生密切相关 DOT1L的一种药理抑制剂目前正在进行临床试验。该项目将调查 在IDH介导的小鼠白血病模型中是否需要DOT1L (SA1)以及详细分析患者染色质和基因表达的变化 样本(SA2)。最后，该项目旨在确定H3K79(SA3)的一种去甲基酶。

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).