Targeting protein acetylation as a therapeutic approach for MDS

靶向蛋白质乙酰化作为 MDS 的治疗方法

基本信息

批准号：
10379453
负责人：
LING LI
金额：
$ 43.25万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
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：
2018-03-03 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379453
关键词：
Acetylation Acute Myelocytic Leukemia Agonist Bone Marrow CD34 gene Catalysis Catalytic Domain Cell Line Cell Maintenance Cell Proliferation Cells DNA DNA Methylation Deacetylase Deacetylation Decitabine Development Dioxygenases Disease Dysmyelopoietic Syndromes Dysplasia Ectopic Expression Elderly Engraftment Enzymes Epigenetic Process Fostering Functional disorder Future Gene Expression Genes Genetic Growth Hematologic Neoplasms Hematological Disease Hematopoiesis Hematopoietic Hematopoietic stem cells Human Hypermethylation Impairment Ineffective Hematopoiesis Knock-out Knockout Mice Knowledge Lead Lysine Maintenance Malignant - descriptor Mass Spectrum Analysis Mediating Modeling Morphology Mus Mutagenesis Mutate Mutation Myelogenous NUP98 gene Pathogenicity Patients Peripheral Pharmacology Population Production Protein Acetylation Proteins RNA Interference RNA interference screen Regulation Relapse Residual state Risk Role SIRT1 gene Specimen Stress Testing Tetanus Helper Peptide Therapeutic Therapeutic Intervention Transplantation Work base cancer stem cell cell transformation clinically relevant cytopenia demethylation high risk improved in vivo knock-down loss of function model development mouse model mutant novel older patient patient population peripheral blood progenitor self-renewal stem cell growth stem cells targeted treatment therapeutically effective therapy development whole genome

项目摘要

Project Summary Myelodysplastic syndromes (MDS) are hematopoietic disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and a propensity for progression to acute myeloid leukemia (AML). MDS remains incurable by existing nontransplant therapy, which is the only option for MDS patients over 60 years old. An increasing number of clonal-analysis studies provide direct evidence that, in MDS, cells of the entire bone marrow are clonally derived from a single hematopoietic stem cell (HSC) or early myeloid progenitor. These aberrant MDS hematopoietic stem and progenitor cells (HSPCs) reportedly resist therapy and expand causing relapse. Thus, improved understanding of mechanisms regulating MDS HSPCs maintenance could foster development of therapies targeting MDS HSPCs. The DNA demethylation enzyme Tet methylcytosine dioxygenase 2 (TET2) reportedly protects normal HSCs from transformation into disease-initiating clones in hematological malignancies. We recently found that protein levels of SIRT1, a deacetylase that contributes to normal HSC maintenance under stress conditions, significantly decreased in MDS CD34+ cells, a population highly enriched for MDS HSPCs. Using loss-of- function and mutagenesis studies, we identified a novel mechanism that SIRT1-deficiency induces TET2 hyperacetylation, leading to TET2 dysfunction in MDS cells. We also found that SIRT1 activation blocked MDS cell proliferation in a TET2-dependent manner. Importantly, our preliminary studies also show that TET2 acetylation levels increase in human MDS specimens expressing below normal SIRT1 protein levels. Based on these findings, we hypothesize that, in the absence of TET2 mutations, SIRT1-deficiency induces TET2 dysfunction due to unregulated hyperacetylation, enabling MDS HSPCs maintenance, and accordingly, that SIRT1-induced TET2 deacetylation could ablate MDS HSPCs. To test our hypothesis, we will: 1) determine the pathogenic roles of SIRT1 and TET2 in MDS maintenance using genetic mouse models; 2) define upstream and downstream factors of the SIRT1/TET2 axis in MDS cells; and 3) determine whether SIRT1 activation alone or in combination with a hypomethylating agent that is currently first-line treatment for older, high risk MDS patients can ablate MDS HSPCs. We expect that our studies will uncover functional interaction between SIRT1 and TET2 and reveal how both factors govern MDS HSPC growth and self-renewal. These studies will close the knowledge gap relevant to how MDS-initiating clones acquire a growth advantage during MDS development and may identify more effective therapeutic strategy for ablating MDS disease- propagating cells by targeting SIRT1.

项目摘要骨髓增生性综合征（MDS）是造血疾病，其特征是无效的造血作用，周围细胞质细胞减少症，以及向急性髓样白血病（AML）进展的倾向。 MDS仍然存在现有的非移植疗法无法治愈，这是60岁以上MDS患者的唯一选择。一个越来越多的克隆分析研究提供了直接证据，表明在MDS中，整个骨骼的细胞骨髓是源自单个造血干细胞（HSC）或早期髓样祖细胞的克隆。这些据报道复发。因此，对调节MDS HSPCS维护的机制的提高理解可以促进靶向MDS HSPC的疗法的开发。据报道从血液系统恶性肿瘤中的疾病引发克隆的转化。我们最近发现蛋白质 SIRT1的水平，一种脱乙酰基酶，在应力条件下有助于正常的HSC维持， MDS CD34+细胞的显着降低，这是高度富含MDS HSPC的种群。使用 - 功能和诱变研究，我们确定了一种新的机制，即SIRT1缺乏诱导TET2 高乙酰化，导致MDS细胞中TET2功能障碍。我们还发现SIRT1激活阻断了MD 细胞增殖以TET2依赖性方式。重要的是，我们的初步研究还表明TET2 乙酰化水平的增加在表达正常SIRT1蛋白水平的人类MDS标本中。基于这些发现，我们假设在没有TET2突变的情况下，SIRT1缺乏诱导 TET2功能障碍由于不受管制的高乙酰化而引起的MDS HSPC维护，因此 SIRT1诱导的TET2脱乙酰化可以消除MDS HSPC。为了检验我们的假设，我们将：1）使用遗传小鼠模型确定SIRT1和TET2在MDS维持中的致病作用； 2）定义MDS细胞中SIRT1/TET2轴的上游和下游因子； 3）确定是否 SIRT1单独激活或与当前是一线治疗的低甲基化剂相结合较大的高风险MDS患者可以消除MDS HSPC。我们预计我们的研究将发现功能 SIRT1与TET2之间的相互作用，并揭示了这两个因素如何控制MDS HSPC的增长和自我更新。这些研究将缩小与MDS发射克隆如何获得增长优势有关的知识差距在MDS开发过程中，可以确定消除MDS疾病的更有效的治疗策略 - 通过靶向SIRT1来传播细胞。