Role of branched-chain amino catabolism in lymphopoiesis and lymphomagenesis

支链氨基分解代谢在淋巴细胞生成和淋巴瘤发生中的作用

基本信息

批准号：
9461496
负责人：
Mario R Fernandez
金额：
$ 6.52万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9461496
关键词：
Acetates Acetoacetates Acetyl Coenzyme A Acute Affect Apoptosis B Cell Proliferation B-Cell Development B-Cell Lymphomas B-Lymphocytes Branched-Chain Amino Acids Burkitt Lymphoma CD19 gene Carbon Catabolism Cell Line Cell Maturation Cell Survival Cells Chronic Citric Acid Cycle Definity Dependence Development Disease Doxycycline Elements Engraftment Enterobacteria phage P1 Cre recombinase Enzymes FADH2 Fetal Liver Flow Cytometry Generations Genes Genetic Transcription Genetic study Glucose Glucose Transporter Glutamates Glutamine Glycolysis Goals Growth Hematopoietic stem cells Homeostasis Human Image Impairment Isoleucine Knock-out Leucine Lymphoma Lymphomagenesis Lymphopoiesis MYCN gene Maintenance Malignant - descriptor Malignant Neoplasms Messenger RNA Metabolic Metabolic Pathway Mitochondria Modeling Molecular Mus NADH Nutrient Oncoproteins Pathway interactions Pharmacology Study Play Precancerous Conditions Premalignant Proteins Reporter Respiration Retroviridae Role Supplementation Testing Tetanus Helper Peptide Tetracyclines Therapeutic Tissues Trans-Activators Transgenic Mice Transplantation Ursidae Family Valine alpha ketoglutarate cancer cell cancer prevention cancer therapy cell growth congenic fatty acid biosynthesis feeding fetal stem cell gabapentin human model inhibitor/antagonist knock-down malignant lymphocyte malignant state mouse model nanoluciferase neoplastic neoplastic cell novel novel therapeutics overexpression propionyl-coenzyme A public health relevance senescence succinyl-coenzyme A transcription factor transport inhibitor tumor uptake

项目摘要

DESCRIPTION (provided by applicant) Cancer cells rewire metabolic pathways to drive the uptake and/or catabolism of nutrients that sustain the high energetic demands needed for their growth (mass) and rapid rates of proliferation. Myc oncoproteins function as transcription factors and are activated in over half of all human cancers. Myc induces the transcription of several genes involved in glycolysis and glutaminolysis, including those encoding transporters of glucose, glutamine, lactate and branched-chain amino acids (BCAA: valine, leucine and isoleucine, via LAT1/SLC7A5). Tumors driven by Myc are addicted to and utilize L-glutamine to feed carbon intermediates into the Krebs cycle. We reasoned that Myc would also control the catabolism of BCAAs, which also provides key metabolic intermediates, specifically acetoacetate, acetyl-CoA, propionyl-CoA/succinyl-CoA, NADH and FADH2. In support of this notion, our new studies of Eμ-Myc transgenic mice, a validated model of human B cell Burkitt lymphoma (BL) that bear MYC/Ig translocations, and of BL cells, demonstrate that: (i) premalignant and neoplastic Myc-expressing B cells express elevated mRNA and protein levels of Bcat1, which is a bona fide Myc transcription target and the first enzyme in BCAA catabolism; (ii) elevated levels of several other enzymes that direct BCAA catabolism are evident in Eμ-Myc B cells and BL; (iii) BCAT1 knockdown impairs the growth, survival and clonogenicity of BL cells; (iv) treatment with Gabapentin, a known BCAT1 inhibitor, impairs the growth and survival of Eμ-Myc lymphoma and of BL, but not of normal B cells. These findings support the hypothesis that BCAT1 is necessary for the development and maintenance of Myc-driven lymphoma. In Specific Aim 1, we will use mouse models to test if Bcat1 plays essential, intrinsic roles in B lymphopoiesis and homeostasis, and if Bcat1 loss affects B cell proliferation and survival. In Specific Aim 2, we will test if Bcat1 is necessary for the development and maintenance of Myc-driven lymphomagenesis. Here we will assess the effects of Bcat1 loss: (i) on the proliferation and survival of pre-malignant Eμ-Myc B cells; (ii) on lymphoma onset and overall survival; and (iii) on maintenance of the malignant state. In Specific Aim 3, we will defin the metabolic perturbations that ensue following chronic versus acute Bcat1 loss or depletion in normal B cells, Eμ-Myc lymphomas and BL cell lines. Here we will assess changes in the steady-state levels and flux of metabolites derived from BCAAs, and possible alterations in mitochondrial respiration, glycolysis and nutrient uptake. In addition, the effects of Bcat1 loss o depletion on the sensitivity of mouse and human lymphomas to glycolytic, OXPHOS and lactate transport inhibitors will be determined. We submit that these studies will establish BCAA catabolism as a novel therapeutic vulnerability for human tumors with MYC/MYCN involvement and that they will offer new avenues for cancer prevention and treatment.

描述（由适用提供的）癌细胞重新代谢途径，以驱动养分的摄取和/或分解代谢，从而维持其生长所需的高能量需求（质量）和快速增殖率。 MYC癌蛋白起转录因子的作用，并在所有人类癌症的一半以上被激活。 MYC诱导了参与糖酵解和谷氨酰胺溶解的几个基因的转录，包括编码葡萄糖，谷氨酰胺，乳糖酸盐和分支链氨基酸转运蛋白的转录（BCAA：Valine，Leucine和Isopoine and Isopoine and Isopoine and Isopoine and lat1/Slc7a5）。由MYC驱动的肿瘤被添加到并利用L-谷氨酰胺将碳中间体喂入克雷布斯循环中。我们认为MYC还将控制BCAA的分解代谢，该分解代谢还提供了关键的代谢中间体，特别是乙酰乙酸，乙酰辅酶A，丙基-COA/丙酰氧基-COA/琥珀酰-COA，NADH和FADH2。为了支持这一概念，我们对Eμ-Myc转基因小鼠的新研究，这是一个带有MYC/IG易位和BL细胞的人类B细胞Burkitt淋巴瘤（BL）的验证模型，它证明了：（i）表达bcAT的MRNA和蛋白质的bbcaTA和蛋白质的bbcACA AaaA，这是BCACA A的bonaa fide，这是：（I）分解代谢；（ii）在Eμ-Myc B细胞和BL中证明了直接BCAA分解代谢的其他几种其他几种酶的水平升高；（iii）BCAT1敲低会损害BL细胞的生长，存活和结构性；（iv）使用已知的BCAT1抑制剂Gabapentin治疗，会损害Eμ-Myc淋巴瘤和BL的生长和存活，而BL的生长和存活率则损害了正常B细胞的生长和存活。这些发现支持以下假设：BCAT1对于MYC驱动的淋巴瘤的发展和维持是必要的。具体的目标1，我们将使用小鼠模型来测试BCAT1在B淋巴细胞和稳态中是否扮演着必不可少的内在作用，以及BCAT1损失是否影响B细胞增殖和存活。在特定的目标2中，我们将测试BCAT1是否需要用于开发和维持MYC驱动的淋巴细胞化作用。在这里，我们将评估BCAT1损失的影响：（i）对eμ-myc B细胞的增殖和存活；（ii）淋巴瘤发作和总生存期；（iii）维持恶性国家。在特定的目标3中，我们将定义代谢扰动，这些扰动在正常B细胞，Eμ-Myc淋巴瘤和BL细胞系中强制执行慢性BCAT1损失或急性BCAT1损失或耗竭。在这里，我们将评估源自BCAA的代谢产物的稳态水平和通量的变化，以及线粒体呼吸，糖酵解和营养摄取的可能改变。此外，将确定BCAT1损失O部署对小鼠和人淋巴瘤对糖酵解，Oxphos和裂解转运抑制剂的敏感性的影响。我们认为，这些研究将确定BCAA分解代谢是一种具有MYC/MYCN参与的人类肿瘤的新型治疗脆弱性，它们将为预防癌症和治疗提供新的途径。