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.

项目概要骨髓增生异常综合征（MDS）是一种以无效造血为特征的造血系统疾病，外周血细胞减少症，以及进展为急性髓系白血病 (AML) 的倾向。 MDS 残留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由单个造血干细胞（HSC）或早期骨髓祖细胞克隆衍生而来。这些据报道，异常的 MDS 造血干细胞和祖细胞 (HSPC) 会抵抗治疗并扩大导致复发。因此，提高对 MDS HSPC 维持调节机制的理解可以促进开发针对 MDS HSPC 的疗法。据报道，DNA 去甲基化酶 Tet 甲基胞嘧啶双加氧酶 2 (TET2) 可保护正常 HSC 从转化为血液恶性肿瘤中的疾病起始克隆。我们最近发现蛋白质 SIRT1 的水平，一种脱乙酰酶，有助于压力条件下 HSC 的正常维持， MDS CD34+ 细胞（MDS HSPC 高度富集的群体）显着减少。使用损失- 通过功能和诱变研究，我们发现了 SIRT1 缺陷诱导 TET2 的新机制过度乙酰化，导致 MDS 细胞中 TET2 功能障碍。我们还发现 SIRT1 激活可阻断 MDS 细胞增殖以 TET2 依赖性方式进行。重要的是，我们的初步研究还表明 TET2 表达低于正常 SIRT1 蛋白水平的人类 MDS 样本中乙酰化水平增加。基于这些发现，我们假设，在没有 TET2 突变的情况下，SIRT1 缺陷会诱导由于不受调节的过度乙酰化导致 TET2 功能障碍，使 MDS HSPC 得以维持，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轴的上游和下游因素； 3) 确定是否 SIRT1 单独激活或与目前一线治疗的低甲基化药物联合使用老年、高危 MDS 患者可以消融 MDS HSPC。我们期望我们的研究能够揭示功能性 SIRT1 和 TET2 之间的相互作用，并揭示这两个因素如何控制 MDS HSPC 生长和自我更新。这些研究将缩小与 MDS 起始克隆如何获得生长优势相关的知识差距在 MDS 发展过程中，可能会确定更有效的治疗策略来消除 MDS 疾病 - 通过靶向 SIRT1 来增殖细胞。