Inactivating EVI1 for the Treatment of Myelodysplastic *

灭活 EVI1 用于治疗骨髓增生异常 *

• 批准号: 7487814
• 负责人: Giuseppina Nucifora
• 金额: $ 36.74万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487814
• 关键词: Acute; Acute Myelocytic Leukemia; Affect; Age; Anemia; Animal Model; Antineoplastic Agents; Aplastic Anemia; Apoptosis; Arsenic Trioxide; Biochemical; Biological; Biological Assay; Blast Cell; Blood Platelets; Blood Transfusion; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Caring; Cell Cycle; Cell Line; Cells; Cessation of life; Chromosomal Rearrangement; Chromosome Band; Chromosome Banding; Chromosomes, Human, Pair 3; Chronic Myeloid Leukemia; Complex; DNA Sequence Rearrangement; Defect; Diagnosis; Disease; Disease Progression; Doctor of Philosophy; Dysmyelopoietic Syndromes; EVI1 gene; Elderly; Erythropoiesis; Event; Fanconi' s Anemia; Frequencies; Genes; Genetic; Genomics; Harvest; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hemorrhage; Hypercellular Bone Marrow; Immunoprecipitation; Impairment; Incidence; Ineffective Hematopoiesis; Infection; Life Expectancy; Maintenance Therapy; Malignant Neoplasms; Medical; Modeling; Molecular; Mus; Numbers; Organ; Pancytopenia; Pathway interactions; Patients; Pharmacotherapy; Phase; Population; Qualifying; Reporter Genes; Repression; Research Personnel; Risk; Role; Site; Staging; Stem cells; Symptoms; Syndrome; System; Thinking; Thrombocytopenia; Time; Work; age group; base; cell growth; chemotherapy; chromosome 5 loss; cytokine; cytopenia; design; human disease; improved; older patient; outcome forecast; programs; response; 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，在血液系统恶性肿瘤中的年发病率很高，每年约有1.4万新诊断病例。约30%-40%的MDS进展为急性髓系白血病(AML)。然而，大多数患者在3-5年内死于感染或出血或治疗并发症。随着医疗保健水平的提高，人们预期寿命的延长，MDS的发病率显著增加，此时MDS的发病率(约5/10万)高于同年龄段的慢性粒细胞白血病(CML)或AML。导致这种疾病的基因事件尚不清楚，但染色体带3 Q26的易位是一种反复出现的异常，在约10%的MDS中可见。这个基因组位置包含EVI1，这是一种在MDS中通过染色体重排而不适当地激活的基因。EVI1阳性的MDS患者会出现致命性的造血缺陷，并迅速演变为AML，通常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，细胞凋亡率增加。随着疾病的发展，细胞失控增殖增加，凋亡减少，保持未成熟状态，原始细胞数量增加。缺乏复制MDS的动物模型严重限制了我们对这种疾病的了解。 我们小组最近的工作通过在小鼠骨髓(BM)细胞中强制表达EVI1，产生了一个重要的MDS动物模型。小鼠表现出MDS的特征，包括骨髓细胞增多，骨髓细胞凋亡，严重的细胞减少和贫血。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，因此提供了一种独特的系统来在仍有可能治疗的阶段了解疾病。对该模型的初步研究已经给出了关于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阳性的小鼠中，疾病从红系受损的存活早期发展到以贫血、细胞凋亡、严重的细胞减少、骨髓细胞凋亡为特征的始终致命的晚期。具体目标旨在确定这一进展中的关键步骤，这些步骤可用于阻止MDS的进展，并跟踪MDS患者的治疗反应。它们包括鉴定EVI1阳性骨髓细胞中破坏造血的分子途径(第一个目的)和被EVI1激活或抑制的基因(第二个目的)。第三个目标将集中在三氧化二砷在治疗EVI1阳性MDS中的作用以及分离抑制EVI1的小分子。