METABOLIC REGULATION IN LEUKEMIA-INITIATING CELLS

白血病起始细胞的代谢调节

基本信息

批准号：
10210323
负责人：
Daisuke Nakada
金额：
$ 46.19万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10210323
关键词：
1p36 5&apos -AMP-activated protein kinase Ablation Acetates Acetyl Coenzyme A Acute Myelocytic Leukemia Acute leukemia Adult Age Anabolism Animal Model Binding Proteins Biological Assay Bromodomain CRISPR/Cas technology Catabolism Cell model ChIP-seq Clustered Regularly Interspaced Short Palindromic Repeats Coenzyme A Ligases Cyclic AMP-Dependent Protein Kinases Data Defect Enzymes Epigenetic Process FLT3 gene Family member Funding Gene Expression Genes Genetic Transcription Genetic study Goals Hematopoietic stem cells Histone Acetylation Histones Homeostasis Human Impairment Lead Link MLL-AF9 Mediating Metabolic Metabolic Pathway Metabolic stress Metabolism Methods Modeling Mus Patients Pharmacology Prognosis Protein Kinase Proteins Regulation Sampling Testing Therapeutic Xenograft Model Xenograft procedure acute myeloid leukemia cell base combinatorial dietary restriction epigenetic drug epigenome experimental study genetic approach glucose metabolism inhibitor/antagonist innovation insight leukemia leukemia initiating cell leukemia treatment leukemogenesis metabolomics mouse model novel novel therapeutics older patient patient derived xenograft model pre-clinical protein kinase inhibitor recruit stem cells synergism therapeutic target

项目摘要

AML is the most common acute leukemia in adults, and it appears increasingly with age. Despite overall improvement in the treatment of leukemia, AML still carries a devastating prognosis for elderly patients (less than 10% of patients survive for 5 years). Thus, new therapies for AML are necessary. AMPK is a metabolic regulator that promotes catabolism and inhibits anabolism, thereby maintaining metabolic homeostasis upon metabolic stress. Using mouse models and AMPK inhibitors, we demonstrated that AMPK inhibition renders AML sensitive to metabolic stress induced by dietary restriction (Saito et al. Cell Stem Cell. 2015). During this study, we noticed that AMPK deletion reduces acetyl-coA and histone acetylation in AML (Fig. 2), concomitant with decreased expression of critical leukemia-promoting genes such as Myc. Importantly, chromatin immunoprecipitation and sequencing (ChIP-seq) revealed that AMPK deletion reduces the occupancy of acetylated histones, all of which marks active genes and recruits transcriptional regulators. We thus hypothesized that AMPK links metabolism to epigenetics in AML by maintaining histone acetylation. In aim 1 we will determine whether the occupancy of transcriptional regulators in AML is regulated by AMPK. In aim 2, we will determine how metabolites and the metabolic enzymes that produces acetyl-coA regulate histone acetylation. In aim 3, we will determine how AMPK-mediated histone acetylation regulates human AML, by generating patient-derived xenograft models of AML. Taken together, this proposal will establish the link between metabolism and epigenetics, more specifically the links between acetyl-CoA metabolism, AMPK, and histone acetylation. We hypothesize that these interactions are essential to recruit transcriptional regulators to key leukemogenic genes. In the next funding cycle, we anticipate to unveil new insights that will inform us on how metabolic regulators could be targeted to sensitize AML to epigenetic drugs, paving the way to novel combinatorial therapies.

AML是成年人中最常见的急性白血病，随着年龄的增长，它似乎越来越多。尽管总体而言改善白血病的治疗，AML仍然对老年患者进行毁灭性的预后（较少超过10％的患者生存了5年）。因此，需要新的AML疗法。 AMPK是代谢促进分解代谢并抑制合成代谢的调节剂，从而维持代谢稳态代谢压力。使用鼠标模型和AMPK抑制剂，我们证明了AMPK抑制剂对饮食限制引起的代谢应激敏感的AML（Saito等人细胞干细胞。2015）。在此期间研究，我们注意到AMPK缺失会降低AML中的乙酰辅酶A和组蛋白乙酰化（图2），伴随随着临界白血病基因（如MYC）的表达降低。重要的是，染色质免疫沉淀和测序（CHIP-SEQ）表明，AMPK缺失减少乙酰化组蛋白，所有这些都标记了活性基因和募集转录调节剂。我们这样假设AMPK通过维持组蛋白乙酰化将代谢与AML的表观遗传学联系起来。在目标1中我们将确定AML中转录调节剂的占用率是否受AMPK的调节。在AIM 2中，我们将确定如何产生乙酰-COA调节组蛋白的代谢产物和代谢酶乙酰化。在AIM 3中，我们将确定AMPK介导的组蛋白乙酰化如何通过生成AML的患者衍生异种移植模型。综上所述，该提议将建立代谢和表观遗传学，更具体地说是乙酰-COA代谢，AMPK和组蛋白之间的联系乙酰化。我们假设这些相互作用对于招募转录调节器至关键至关重要白血病基因。在下一个资金周期中，我们预计将揭示新的见解，以告知我们如何代谢调节剂可以旨在使AML对表观遗传药物敏感，从而为新颖的道路铺平了道路组合疗法。