Inactivating EVI1 for the Treatment of Myelodysplastic *

灭活 EVI1 用于治疗骨髓增生异常 *

• 批准号: 7128100
• 负责人: Giuseppina Nucifora
• 金额: $ 37.84万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7128100
• 关键词: apoptosis; arsenic; bone marrow disorder; cell differentiation; cell line; cell proliferation; cytokine; disease /disorder model; gel mobility shift assay; gene induction /repression; hematopoiesis; human tissue; immunoprecipitation; laboratory mouse; model design /development; pathologic process; reporter genes; small molecule

DESCRIPTION (provided by Applicant): Myelodysplastic syndrome (MDS) is a group of stem cell malignancies most frequent among elderly patients and has a high annual incidence among hematological malignancies with approximately 14,000 new cases diagnosed every year. About 30%-40% of MDS progresses to acute myeloid leukemia (AML). However, the majority of patients succumb from infection or bleeding or treatment complications within 3-5 years. With the increase of life expectancy due to improving medical care, there has been a significant increase in the frequency of MDS and at this time the incidence of MDS (about 5 per 100,000) is higher than that of chronic myelogenous leukemia (CML) or AML in the same age group. The genetic events that drive this disease are not known, however a translocation of chromosome band 3 q26 is a recurring abnormality seen in about 10% of MDS. This genomic site contains EVI1, a gene inappropriately activated in MDS by the chromosomal rearrangement. EVI1-positive MDS patients develop fatal hematopoietic defects rapidly evolving to AML and in general their survival is less than one year. In terms of the biological mechanisms which characterize MDS, it is generally thought that the MDS cell has impaired differentiation and increased apoptosis. As the disease evolves, the cells have increased deregulated proliferation and decreased apoptosis, remain immature, and the number of blast cells increases. The lack of an animal model that reproduces MDS has strongly limited our understanding of this disease. Recent work by our group has generated a significant animal model of MDS by forcing the expression of EVI1 in murine bone marrow (BM) cells. The mice show features of MDS including hypercellular BM, BM apoptosis, and severe cytopenia and anemia. In contrast to what observed in patients, the EVI1-ppsitive murine MDS does not evolve to AML and therefore provides a unique system to understand the disease at a stage which is still potentially treatable. Preliminary studies with this model have given clear clues about molecular pathways that affect erythropoiesis, platelet formation, and cell cycling immediately after expression of EVI1 and suggest that in the EVI1-positive mice the disease progresses from a viable early stage in which the erythropoietic lineage is compromised, to an always fatal late stage characterized by anemia, apoptosis, severe cytopenia, BM apoptosis, leading to death. The specific aims are designed to identify key steps in this progression that could be used to block the advancement of MDS and to follow the response to treatment of MDS patients. They include the identification of the molecular pathways that disrupt hematopoiesis in EVI1-positive BM cells (first aim) and of the genes that are activated or repressed by EVI1 (second aim). The third aim will be focused on the role of arsenic trioxide in the treatment of EVI1-positive MDS and on the isolation of small molecules that inhibit EVI1.

描述（由申请人提供）： 骨髓增生异常综合征（MDS）是一组在老年患者中最常见的干细胞恶性肿瘤，也是血液系统恶性肿瘤中年发病率较高的疾病，每年约有 14,000 例新诊断病例。大约 30%-40% 的 MDS 会进展为急性髓系白血病 (AML)。然而，大多数患者在 3-5 年内因感染、出血或治疗并发症而死亡。随着医疗保健改善导致预期寿命增加，MDS的发病率显着增加，此时MDS的发病率（约每10万人中5例）高于同年龄组的慢性粒细胞白血病（CML）或AML。导致这种疾病的遗传事件尚不清楚，但染色体带 3 q26 易位是一种反复出现的异常，在约 10% 的 MDS 中可见。该基因组位点包含 EVI1，这是一种在 MDS 中因染色体重排而被不当激活的基因。 EVI1 阳性 MDS 患者会出现致命的造血缺陷，并迅速发展为 AML，一般来说，他们的生存期不到一年。就MDS的生物学机制而言，一般认为MDS细胞分化受损，细胞凋亡增加。随着疾病的发展，细胞增殖失调增加，细胞凋亡减少，保持不成熟，并且母细胞数量增加。缺乏重现 MDS 的动物模型极大地限制了我们对这种疾病的了解。 我们小组最近的工作通过迫使 EVI1 在小鼠骨髓 (BM) 细胞中表达，建立了重要的 MDS 动物模型。小鼠表现出骨髓增生异常综合征的特征，包括骨髓细胞增多、骨髓细胞凋亡以及严重的血细胞减少和贫血。与在患者中观察到的情况相反，EVI1 阳性的小鼠 MDS 不会演变为 AML，因此提供了一个独特的系统来了解处于仍可治疗阶段的疾病。使用该模型的初步研究已经提供了关于在 EVI1 表达后立即影响红细胞生成、血小板形成和细胞周期的分子途径的明确线索，并表明在 EVI1 阳性小鼠中，疾病从红细胞生成谱系受损的可行早期阶段发展到以贫血、细胞凋亡、严重血细胞减少、BM 为特征的始终致命的晚期阶段。 细胞凋亡，导致死亡。 具体目标旨在确定这一进展中的关键步骤，可用于阻止 MDS 的进展并跟踪 MDS 患者对治疗的反应。它们包括鉴定破坏 EVI1 阳性 BM 细胞造血功能的分子途径（第一个目标）以及被 EVI1 激活或抑制的基因（第二个目标）。第三个目标将集中于三氧化二砷在治疗 EVI1 阳性 MDS 中的作用以及抑制 EVI1 的小分子的分离。