Targeting Metabolic Liabilities of Leukemia-Initiating Cells (R01CA230631)

针对白血病起始细胞的代谢能力 (R01CA230631)

基本信息

批准号：
10865405
负责人：
Jian Xu
金额：
$ 40.8万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
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 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10865405
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.

项目摘要癌症进展中表观遗传学与代谢之间的功能关系尚未仔细检查。许多催化DNA或组蛋白修饰的表观遗传酶易于变化新陈代谢的共同材料，但对表观遗传学的改变以及如何影响细胞遗传学知之甚少癌症进展过程中的代谢。 EZH2的突变，组蛋白H3赖氨酸27甲基转移酶是在髓样恶性肿瘤中经常发现，并与预后不良相关。我们最近开发了一个新的髓样肿瘤的小鼠模型通过失活EZH2和激活致癌NRA（G12D）。尽管仅G12d就导致腹腔滞留，EZH2失活显着加速了疾病进展导致骨髓纤维化，白血病转化和死亡率。忠实地概括的模型白血病进展，我们意外地确定了分支链氨基酸（BCAA）代谢是最大的 EZH2缺乏性白血病发射细胞（LICS）中的代谢途径显着上调。 BCAT1，第一个酶催化BCAA跨度，在造血中受EZH2的抑制，并异常激活 EZH2缺乏小鼠和人类的髓样肿瘤。增加BCAT1可促进BCAA生产 lics，导致激活的MTOR信号传导。 BCAT1的遗传和药理抑制选择性损害EZH2缺乏的lIC，构成了代谢脆弱性。这些发现首次连接 EZH2在癌症进展中代谢途径改变的失调。该项目的目的是通过关注BCAA的作用来阐明控制LIC代谢责任的因果机制 EZH2缺陷型髓样肿瘤中的代谢。中心假设是EZH2缺乏引起通过激活BCAT1和BCAA代谢来重新代谢，以创造代谢依赖性，并 BCAT1的抑制作用将通过禁用EZH2缺陷的代谢责任来选择性地消除lics。 lics。该假设是根据我们的初步研究提出的，使用了体内模型白血病的进展和新发现的表观遗传学和代谢之间的分子联系。在这些初步数据的指导下，该假设将通过三个特定目的检验：1）定义功能 BCAT1在EZH2缺乏性诱导的髓样肿瘤中的作用在体内使用BCAT1敲除和诱导表达鼠标模型。 2）确定EZH2缺乏的LIC表现出代谢的机制依赖BCAA代谢。 3）确定靶向BCAA代谢在人AML中的影响干细胞使用遗传，药理和饮食操纵。这些研究不仅将验证EZH2突变髓样肿瘤的选择性代谢责任，但也发现了新的途径可以利用这有选择地消除lics。这些结果有望提高我们的机械了解癌症进展中表观遗传学与代谢之间的功能关系，以及指导更有效的疗法的设计，以靶向癌细胞的代谢负债。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dissecting Locus-Specific Chromatin Interactions by CRISPR CAPTURE.

通过 CRISPR CAPTURE 剖析位点特异性染色质相互作用。

DOI：
10.1007/978-1-0716-2847-8_7
发表时间：
2023
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Botten,GiovanniA;LeeJr,Michael;Xu,Jian
通讯作者：
Xu,Jian

Light-activated macromolecular phase separation modulates transcription by reconfiguring chromatin interactions.

DOI：
10.1126/sciadv.adg1123
发表时间：
2023-03-31
期刊：
SCIENCE ADVANCES
影响因子：
13.6
作者：
Kim, Yoon Jung;Lee Jr, Michael;Lee, Yi-Tsang;Jing, Ji;Sanders, Jacob T.;Botten, Giovanni A.;He, Lian;Lyu, Junhua;Zhang, Yuannyu;Mettlen, Marcel;Ly, Peter;Zhou, Yubin;Xu, Jian
通讯作者：
Xu, Jian

Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress.

DOI：
10.1016/j.celrep.2020.108087
发表时间：
2020-09-01
期刊：
Cell reports
影响因子：
8.8
作者：
Dai C;Li Q;May HI;Li C;Zhang G;Sharma G;Sherry AD;Malloy CR;Khemtong C;Zhang Y;Deng Y;Gillette TG;Xu J;Scadden DT;Wang ZV
通讯作者：
Wang ZV

SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc-SMPDL3B.

SIRT1通过c-Myc-SMPDL3B调节小鼠胚胎干细胞的鞘脂代谢和神经分化