Epigenetic regulation by microRNA of MDS pathogenesis

MicroRNA对MDS发病机制的表观遗传调控

• 批准号: 9096068
• 负责人: Keisuke Ito
• 金额: $ 25.05万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096068
• 关键词: 3' Untranslated Regions; Ablation; Affect; Attenuated; Biogenesis; Bioinformatics; Biological Assay; Bone Marrow Cells; Cell Line; Cell Proliferation; Cell physiology; Cells; Clinic; Clinical; Clinical Data; Clinical Trials; Custom; DNA Methylation; Data; Data Set; Disease; Down-Regulation; Dysmyelopoietic Syndromes; Ectopic Expression; Epigenetic Process; Event; Evolution; Exhibits; Gene Targeting; Genes; Genetic; Goals; Health; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Human; Hydroxylation; In Vitro; Ineffective Hematopoiesis; Injury; Knockout Mice; Lead; Leukemic Cell; Link; Luciferases; Maintenance; Malignant - descriptor; Messenger RNA; MicroRNAs; Molecular; Molecular Abnormality; Multiple Myeloma; Mus; Myeloid Leukemia; Myeloproliferative disease; Nuclear; Oncogenic; Onset of illness; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Penetrance; Personal Satisfaction; Phenotype; Play; Porifera; Pre-Clinical Model; Proteins; Proto-Oncogenes; Regulation; Regulatory Element; Reporter; Repression; Research; Research Design; Role; Safety; Sampling; Specimen; Stem cells; Supportive care; Survival Rate; Techniques; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Transplantation; Untranslated RNA; Work; Xenograft Model; blood treatment; cohort; effective therapy; epigenetic regulation; gene translocation; genetic manipulation; genome-wide; in vivo; leukemia; leukemogenesis; mouse model; novel; novel therapeutic intervention; oncology; overexpression; pre-clinical trial; programs; reduce symptoms; self-renewal; stem; stem cell biology; stem cell niche; therapeutic target; tumorigenesis

DESCRIPTION (provided by applicant): Myelodysplastic syndrome (MDS) is an incurable stem cell disorder that often progresses to myeloid leukemia. An abnormal epigenetic modulation has been highlighted as playing a crucial part in the pathogenesis, progress, and evolution of this disorder. To date, effective therapy for MDS has proved elusive, with supportive care used to ameliorate symptoms, and hematopoietic stem cell transplantation the only available curative option. MicroRNAs have recently been implicated in hematological malignancies through their inhibition of the expression of specific target genes. In this context, we have identified an oncogenic microRNA that enhances the self-renewal of stem cells and remodels the epigenetic landscape toward hematological malignancies. To better understand through its activity the key pathways involved in stem cell biology and MDS pathogenesis, we propose the following Specific Aims: 1. Determine how TET2 directly contributes to function of an oncogenic microRNA in hematopoiesis We have generated transgenic mice conditionally expressing this newly-identified oncogenic microRNA in the hematopoietic compartment, which in turn exhibits lower levels of ten-eleven translocation gene 2 (TET2) and global 5-hydroxymethylcytosine than control cells. Bioinformatics analyses have consistently identified TET2 as a potential target of this microRNA, whose expression was directly anti-correlated with the levels of TET2 in our large-cohort data set of patients with MDS, leading us to hypothesize that TET2 is its key target. The current proposal aims to elucidate the effect of ectopic expression of TET2 on the hematopoietic phenotypes induced by this microRNA both in vivo and in vitro. We expect our studies will provide a rationale for the therapeutic potential of targeting TET2 for the treatment of hematological malignancies. 2. Test the therapeutic potential of microRNA inhibition in preclinical models of MDS. We have shown a direct correlation between aberrant expression of this microRNA and poor MDS survival rates. Our preliminary findings demonstrated in vitro that blocking this microRNA reduces leukemogenicity in mouse primary leukemic cells and in human leukemia cell lines, accompanied by elevation of TET2, with minimal injury to normal murine hematopoiesis. In this aim, we propose to assess the safety and efficacy of inhibition of microRNA in human primary leukemia samples. We will integrate these findings with the data of ongoing pre-clinical trials in faithful mouse models of myelodysplastic syndrome, and will finally explore the potential to initiate formal clinical trial towards effective eradication of myelodysplastic syndrome. 3. To elucidate mechanistically the key target genes regulated by the microRNA-TET2 pathway: To further understand the consequences of repression of TET2 protein by the microRNA in hematopoiesis, we will examine the effects of aberrant microRNA-TET2 cross-talk on putative targets of TET2 protein. We will focus our analysis on the genetic manipulation of these genes, both in vivo and in vitro, in murine hematopoietic stem cells from transgenic mice, to observe the subsequent effects on MDS pathogenesis induced by microRNA. These proposed studies will not only identify microRNA as a potent proto-oncogene, but will also define aberrations in the microRNA-TET2 regulatory network as one of the most frequent events in hematological malignancies, with important therapeutic implications. This work will be conducted with the support of the following experts; Drs. David E. Avigan (Hematology/Oncology), Jan Vijg (Genetics, Epigenetics and microRNA biogenesis), Julie Teruya-Feldstein (Hemato-pathology), and Toshio Suda (Stem Cells). Importantly, Dr. Paul S. Frenette (Stem Cell niche) is closely supporting our research program along with Dr. Arthur Skoultchi (Epigenetic reprogramming in Hematology).

描述（由申请人提供）：骨髓增生综合征（MDS）是一种无法治愈的干细胞疾病，通常会发展为髓样白血病。异常表观遗传调节被强调为在这种疾病的发病机理，进步和进化中起着至关重要的作用。迄今为止，对MDS的有效疗法已证明是难以捉摸的，并具有用于改善症状的支持性护理，而造血干细胞移植是唯一可用的治疗方法。 MicroRNA最近通过抑制特定靶基因的表达而与血液学恶性肿瘤有关。在这种情况下，我们已经确定了一种致癌性microRNA，可以增强干细胞的自我更新并重塑表观遗传景观，以朝着血液学恶性肿瘤。为了通过其活性更好地理解干细胞生物学和MDS发病机理中涉及的关键途径，我们提出以下具体目的：1。确定TET2如何直接促进造血中的致癌性微生物的功能。 （TET2）和全球5-羟基甲基胞嘧啶而不是对照细胞。生物信息学分析始终将TET2识别为该microRNA的潜在靶标，其表达与MDS患者的大核病数据集直接与TET2的水平直接抗相关，从而使我们假设TET2是其关键目标。当前的建议旨在阐明TET2异位表达对这种microRNA在体内和体外诱导的造血表型的影响。我们预计我们的研究将为靶向TET2治疗血液系统恶性肿瘤的治疗潜力提供理由。 2。在MDS的临床前模型中测试microRNA抑制的治疗潜力。我们已经显示了该microRNA异常表达与MD差的存活率之间的直接相关性。我们的初步发现表明，在体外表明，阻止这种microRNA降低了小鼠原发性白血病细胞和人类白血病细胞系中的白血病性，并伴随着TET2的升高，对正常的鼠血瘤造成了最小的损伤。在此目标中，我们建议评估人类原发性白血病样品中抑制microRNA的安全性和功效。我们将将这些发现与忠实的骨髓增生综合征小鼠模型中正在进行的临床前试验的数据相结合，并最终将探索启动正式临床试验以有效根除骨髓增生综合征的潜力。 3。为了机械阐明由MicroRNA-TET2途径调节的关键靶基因：为了进一步了解造血中microRNA对TET2蛋白抑制的后果，我们将研究异常的MicroRNA-TET2交叉词对TET2蛋白推定靶标的异常的影响。我们将分析将这些基因的遗传操作集中在转基因小鼠的鼠造血干细胞中，以观察MicroRNA诱导的MDS发病机理的后续作用。这些拟议的研究不仅将MicroRNA鉴定为有效的原型癌基因，而且还将将MicroRNA-TET2调节网络中的畸变定义为血液学恶性肿瘤中最常见的事件之一，具有重要的治疗意义。这项工作将在以下专家的支持下进行；博士。 David E. Avigan（血液学/肿瘤学），Jan Vijg（遗传学，表观遗传学和MicroRNA生物发生），Julie Teruya-Feldstein（Hemato-Phology）和Toshio Suda（干细胞）。重要的是，Paul S. Frenette博士（干细胞生态位）与Arthur Skoultchi博士（血液学的表观遗传重编程）密切支持我们的研究计划。