The Role of DLST in Leukemogenesis

DLST 在白血病发生中的作用

基本信息

批准号：
10381276
负责人：
Hui Feng
金额：
$ 7.33万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-07 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381276
关键词：
5&apos -AMP-activated protein kinase Acute Lymphocytic Leukemia Acute T Cell Leukemia Address Affect Animal Model Apoptosis Area Biochemical Biochemical Pathway Biological Assay Cell Proliferation Cell Respiration Cell Survival Cells Citric Acid Cycle DNA Data Dependence Development Dioxygenases Disease Drug resistance Enzymes Epigenetic Process Fishes Gene Silencing Genes Genetic Goals Health Histones Human Impairment Isocitrate Dehydrogenase Lead Leukemic Cell Link Loss of Heterozygosity Malignant Neoplasms Mediating Metabolic Metabolic Pathway Metabolic stress Metabolism Modeling Mus Oncogenic Pathogenesis Pathway interactions Patients Pharmacology Physiological Prognosis Protein Kinase Proteins Proteolysis RNA Interference Recurrent disease Refractory Refractory Disease Regulation of Proteolysis Regulatory Pathway Relapse Reporting Research Resistance Resources Role System T-Lymphocyte Therapeutic Studies Transferase Treatment outcome Xenograft procedure Zebrafish alpha ketoglutarate base cancer cell cofactor demethylation flexibility histone methylation human disease improved in vivo inhibitor/antagonist innovation insight knock-down leukemia leukemia treatment leukemogenesis metabolomics mortality neoplastic cell novel novel therapeutic intervention novel therapeutics overexpression patient derived xenograft model small molecule small molecule inhibitor succinyl-coenzyme A targeted treatment therapeutic evaluation tumor tumor initiation tumor metabolism tumor progression tumorigenesis ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Despite treatment improvements, leukemia-associated mortality is still high owing to drug resistance and disease relapse. Metabolic reprogramming is a hallmark of cancer, and represents an exciting new area of targeted therapy. Therefore, identification of the key enzyme responsible for metabolic reprogramming and elucidation of its mechanisms of action in treatment-resistant leukemic cells could lead to novel therapeutic strategies against the unique metabolic dependence of these cancer cells. We recently reported that dihydrolipoamide S-succinyltransferase (DLST) serves as a critical metabolic “oncorequisite” enzyme in MYC- driven leukemogenesis. MYC-dependent T-acute lymphoblastic leukemia (T-ALL) cells reprogram metabolism by stabilizing DLST protein, and rely heavily on its elevated levels for proliferation and survival. Heterozygous loss of dlst in zebrafish does not impair development yet significantly delays the onset of MYC-induced T-ALL that resembles a major subtype of human disease with poor prognosis. DLST is a transferase in the tricarboxylic acid (TCA) cycle and mediates the conversion of α-ketoglutarate (α-KG) to succinyl-CoA. α-KG is a key cycle intermediate that simultaneously functions as an obligatory cofactor for α-KG-dependent dioxygenases (α-KGDO, e.g., demethylases), thus linking cellular metabolism with epigenetic controls of the cell. We hypothesize that: DLST protein stabilization accelerates α-KG conversion, enhances TCA cycle function, and suppresses α-KGDO activities, thus promoting leukemic cell proliferation and survival. In Aim 1 of this application we will apply genetic, pharmacological and biochemical approaches to determine the mechanisms by which DLST is stabilized in MYC-overexpressing T-ALL cells and identify novel DLST interactors including its E3 ligase(s). The zebrafish T-ALL model will then be utilized to define the role of key DLST regulators/interactors in T-ALL pathogenesis. In Aim 2, we will combine the analyses of the in vivo zebrafish model and human T-ALL cells to identify the biochemical and epigenetic changes associated with DLST inactivation, as well as functionally characterize key α-KGDO regulated by DLST in T-ALL pathogenesis. In Aim 3, we will investigate the targetability and compensatory pathways of DLST in relapsed/refractory T-ALL by using our newly identified DLST inhibitor and in vivo animal models including murine patient-derived xenografts. The innovation of this application lies in the study of DLST as a novel “oncorequisite” enzyme that regulates both metabolism and epigenetic status of the cell in a physiologically relevant in vivo zebrafish system. Indeed, this innovative system has enabled us to identify MYC and AMP-activated protein kinase as regulators for DLST and isocitrate dehydrogenase 2 as its compensatory gene. This research is significant in that it will deepen our understanding of leukemia pathogenesis and cancer metabolism, as well as the metabolo-epigenetic connections in MYC-dependent leukemic cells, with the long-term goal of developing novel therapeutic strategies against DLST-mediated pathways in cancer cells.

项目概要尽管治疗方法有所改进，但白血病相关死亡率仍然与耐药性和耐药性有关疾病复发。代谢重编程是癌症的一个标志，代表着一个令人兴奋的新领域。因此，需要鉴定负责代谢重编程和的关键酶。阐明其在难治性白血病细胞中的作用机制可能会带来新的治疗方法我们最近报道了针对这些癌细胞独特的代谢依赖性的策略。二氢硫辛酰胺 S-琥珀酰转移酶 (DLST) 是 MYC- 中关键的代谢“致癌必需”酶 MYC 依赖性 T 急性淋巴细胞白血病 (T-ALL) 细胞重编程代谢。通过稳定 DLST 蛋白，并严重依赖其升高的水平进行增殖和存活。斑马鱼中 dlst 的缺失不会损害发育，但会显着延迟 MYC 诱导的 T-ALL 的发生 DLST 是一种类似于人类疾病的主要亚型且预后不良的转移酶。三羧酸 (TCA) 循环并介导 α-酮戊二酸 (α-KG) 转化为琥珀酰辅酶 A。一种关键的循环中间体，同时充当 α-KG 依赖性的必需辅助因子双加氧酶（α-KGDO，例如去甲基酶），从而将细胞代谢与表观遗传控制联系起来我们认为：DLST 蛋白稳定可加速 α-KG 转化，增强 TCA。循环功能，并抑制α-KGDO活性，从而促进白血病细胞增殖和在本应用的目标 1 中，我们将应用遗传、药理学和生化方法来解决生存问题。确定 DLST 在 MYC 过表达 T-ALL 细胞中稳定的机制并鉴定新的然后，将利用 DLST 相互作用因子（包括其 E3 连接酶）来定义 DLST 相互作用因子的作用。 T-ALL 发病机制中的关键 DLST 调节因子/相互作用因子在目标 2 中，我们将结合体内分析。斑马鱼模型和人类 T-ALL 细胞识别与相关的生化和表观遗传变化 DLST 失活，以及 T-ALL 发病机制中 DLST 调节的关键 α-KGDO 的功能特征。在目标 3 中，我们将研究 DLST 在复发/难治性 T-ALL 中的靶向性和补偿途径通过使用我们新发现的 DLST 抑制剂和体内动物模型，包括源自小鼠患者的该应用的创新在于 DLST 作为一种新型“癌必需”酶的研究。调节生理相关的体内斑马鱼细胞的代谢和表观遗传状态事实上，这个创新系统使我们能够将 MYC 和 AMP 激活的蛋白激酶识别为 DLST和异柠檬酸脱氢酶2作为其补偿基因的调节因子，这项研究具有重要意义。它将加深我们对白血病发病机制和癌症代谢以及 MYC 依赖性白血病细胞的代谢-表观遗传联系，长期目标是开发针对癌细胞中 DLST 介导的途径的新治疗策略。