Targeting Metabolic Liabilities of Leukemia-Initiating Cells

针对白血病起始细胞的代谢能力

基本信息

批准号：
10551337
负责人：
Jian Xu
金额：
--
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10551337
关键词：
Acceleration Affect Branched-Chain Amino Acids CRISPR/Cas technology Cancer Control Cancer Patient Cells Clinical Complex DNA Modification Process Data Dependence Development Disease Progression Dysmyelopoietic Syndromes EZH2 gene Enzymes Epigenetic Process Exhibits FRAP1 gene Functional disorder Gene Expression Regulation Genetic Genetic Models Hematologic Neoplasms Hematopoiesis Hematopoietic Neoplasms Hematopoietic stem cells Histone H3 Human Impairment In Vitro Indolent Knock-out Link Lysine Malignant - descriptor Malignant Neoplasms Metabolic Metabolic Control Metabolic Pathway Metabolism Methyltransferase Modeling Molecular Mus Mutation Myelofibrosis Myeloproliferation Myeloproliferative disease Oncogenic Pathway interactions Patients Polycomb Predisposition Production Prognosis Repression Role Signal Transduction Testing Therapeutic Time Work Xenograft Model amino acid metabolism cancer cell cancer initiation conditional knockout design dietary manipulation druggable target effective therapy histone methyltransferase histone modification improved in vivo in vivo Model inducible gene expression inhibitor innovation insight leukemia leukemia initiating cell leukemic transformation loss of function loss of function mutation mortality mouse model mutant overexpression pharmacologic small hairpin RNA stable isotope stem cells targeted treatment therapeutically effective transamination tumor progression

项目摘要

PROJECT SUMMARY The functional relationship between epigenetics and metabolism in cancer progression has not been carefully examined. Many epigenetic enzymes catalyzing DNA or histone modifications are susceptible to changes in co-substrates of metabolism, but little is known about whether and how altered epigenetics influences cellular metabolism during cancer progression. Mutations of EZH2, the histone H3 lysine 27 methyltransferase, are frequently found in myeloid malignancies and correlate with poor prognosis. We recently developed a new mouse model of myeloid neoplasms by inactivation of EZH2 and activation of oncogenic NRas (G12D). While G12D alone led to an indolent myeloproliferation, EZH2 inactivation markedly accelerated disease progression resulting in myelofibrosis, leukemic transformation and mortality. With this model that faithfully recapitulates leukemia progression, we unexpectedly identified branched-chain amino acid (BCAA) metabolism as the most significantly upregulated metabolic pathway in EZH2-deficient leukemia-initiating cells (LICs). BCAT1, the first enzyme catalyzing BCAA transamination, is repressed by EZH2 in hematopoiesis and aberrantly activated in EZH2-deficient myeloid neoplasms in mice and humans. Increased BCAT1 promotes BCAA production in LICs, resulting in activated mTOR signaling. Genetic and pharmacological inhibition of BCAT1 selectively impairs EZH2-deficient LICs and constitutes a metabolic vulnerability. These findings for the first time connect dysregulation of EZH2 with altered metabolic pathways in cancer progression. The objective of this project is to elucidate the causal mechanisms controlling metabolic liabilities of LICs by focusing on the role of BCAA metabolism in EZH2-deficient myeloid neoplasms. The central hypothesis is that EZH2 deficiency induces metabolic rewiring by activating BCAT1 and BCAA metabolism to create a metabolic dependency for LICs, and that inhibition of BCAT1 will selectively eradicate LICs by disabling the metabolic liability of EZH2-deficient LICs. This hypothesis has been formulated on the basis of our preliminary studies using an in vivo model of leukemia progression and a newly discovered molecular link between altered epigenetics and metabolism. Guided by these preliminary data, this hypothesis will be tested by three specific aims: 1) Define the functional role of BCAT1 in EZH2-deficiency-induced myeloid neoplasms in vivo using BCAT1 knockout and inducible expression mouse models. 2) Determine the mechanisms by which EZH2-deficient LICs exhibit a metabolic dependency on BCAA metabolism. 3) Determine the effects of targeting BCAA metabolism in human AML stem cells using genetic, pharmacological and dietary manipulations. Together these studies will not only validate a selective metabolic liability for EZH2-mutant myeloid neoplasms, but also uncover new pathways that can be exploited to selectively eradicate LICs. Such results are expected to advance our mechanistic understanding of the functional relationship between epigenetics and metabolism in cancer progression, and to guide the design of more effective therapies to target the metabolic liabilities of cancer-initiating cells.

项目概要表观遗传学和代谢在癌症进展中的功能关系尚未得到仔细研究检查了。许多催化 DNA 或组蛋白修饰的表观遗传酶很容易受到代谢的共底物，但对于表观遗传学的改变是否以及如何影响细胞知之甚少癌症进展过程中的新陈代谢。 EZH2（组蛋白 H3 赖氨酸 27 甲基转移酶）的突变是常见于骨髓恶性肿瘤并与不良预后相关。我们最近开发了一种新的通过 EZH2 失活和致癌 NRas (G12D) 激活建立的骨髓肿瘤小鼠模型。尽管 G12D 单独导致惰性骨髓增殖，EZH2 失活显着加速疾病进展导致骨髓纤维化、白血病转化和死亡。这个模型忠实地再现了在白血病进展过程中，我们出乎意料地发现支链氨基酸（BCAA）代谢是最重要的代谢 EZH2 缺陷的白血病起始细胞 (LIC) 中的代谢途径显着上调。 BCAT1，第一个催化 BCAA 转氨作用的酶在造血过程中被 EZH2 抑制，并在造血过程中被异常激活小鼠和人类中 EZH2 缺陷的骨髓肿瘤。 BCAT1 增加可促进 BCAA 的产生 LIC，导致 mTOR 信号传导激活。 BCAT1 的遗传和药理学选择性抑制损害 EZH2 缺陷的 LIC 并构成代谢脆弱性。这些发现首次将 EZH2 失调会改变癌症进展中的代谢途径。该项目的目标是通过关注 BCAA 的作用，阐明控制 LIC 代谢负担的因果机制 EZH2 缺陷型骨髓肿瘤的代谢。中心假设是 EZH2 缺陷会导致通过激活 BCAT1 和 BCAA 代谢来重新布线代谢，以产生 LIC 的代谢依赖性，以及抑制 BCAT1 将通过禁用 EZH2 缺陷的代谢能力来选择性地根除 LIC LIC。这一假设是在我们使用体内模型进行的初步研究的基础上提出的。白血病的进展以及新发现的表观遗传学和代谢改变之间的分子联系。在这些初步数据的指导下，该假设将通过三个具体目标进行检验：1）定义函数使用 BCAT1 敲除和诱导研究 BCAT1 在 EZH2 缺陷诱导的体内骨髓肿瘤中的作用表达小鼠模型。 2) 确定 EZH2 缺陷 LIC 表现出代谢的机制对 BCAA 代谢的依赖性。 3) 确定针对人类 AML 中支链氨基酸代谢的影响使用遗传、药理学和饮食操作的干细胞。这些研究一起不仅将验证 EZH2 突变骨髓肿瘤的选择性代谢倾向，同时也揭示了新的途径可以用来选择性地根除低收入国家。这些结果预计将推进我们的机制了解表观遗传学和代谢在癌症进展中的功能关系，并指导设计更有效的疗法来针对癌症起始细胞的代谢负担。