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

• 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
• 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

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 骨髓增生异常综合征（MDS）是以无效造血为特征的造血障碍， 外周血细胞减少和发展为急性髓性白血病（AML）的倾向。MDS仍然 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，在MDS中，整个骨的细胞 骨髓克隆地来源于单个造血干细胞（HSC）或早期骨髓祖细胞。这些 据报道，异常的MDS造血干细胞和祖细胞（HSPC）抵抗治疗并扩增， 复发因此，对调节MDS HSPC维持的机制的更好理解可以促进 开发靶向MDS HSPC的疗法。 据报道，DNA去甲基化酶泰特甲基胞嘧啶双加氧酶2（TET 2）保护正常HSC 从血液恶性肿瘤转化为引发疾病的克隆。我们最近发现这种蛋白质 SIRT 1水平，一种在应激条件下有助于正常HSC维持的脱乙酰酶， 在MDS CD 34+细胞（高度富集MDS HSPC的群体）中，CD 34+细胞显著减少。使用损失- 功能和诱变研究，我们确定了一种新的机制，SIRT 1缺陷诱导TET 2 过度乙酰化，导致MDS细胞中TET 2功能障碍。我们还发现SIRT 1激活阻断MDS 细胞增殖以TET 2依赖的方式。重要的是，我们的初步研究还表明，TET 2 在表达低于正常SIRT 1蛋白水平的人MDS标本中乙酰化水平增加。 基于这些发现，我们假设，在没有TET 2突变的情况下，SIRT 1缺陷诱导了 由于不受调节的超乙酰化导致的TET 2功能障碍，使得MDS HSPC得以维持，因此， SIRT 1诱导的TET 2去乙酰化可以消除MDS HSPCs。为了验证我们的假设，我们将：1） 使用遗传小鼠模型确定SIRT 1和TET 2在MDS维持中的致病作用; 2） 定义MDS细胞中SIRT 1/TET 2轴的上游和下游因素;和3）确定是否 SIRT 1单独激活或与低甲基化剂联合激活，目前低甲基化剂是SIRT 1的一线治疗。 老年、高风险MDS患者可以消融MDS HSPC。我们希望我们的研究能揭示功能性的 SIRT 1和TET 2之间相互作用，并揭示这两种因素如何支配MDS HSPC生长和自我更新。 这些研究将填补与MDS启动克隆如何获得生长优势相关的知识空白 在MDS的发展过程中，并可能确定更有效的治疗策略，消除MDS疾病- 通过靶向SIRT 1繁殖细胞。