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）： 骨髓增生综合征（MDS）是一组干细胞恶性肿瘤，在老年患者中最常见，血液恶性肿瘤的年发病率很高，每年诊断出约14,000例新病例。大约30％-40％的MDS发展为急性髓样白血病（AML）。但是，大多数患者在3 - 5年内屈服于感染或出血或治疗并发症。随着由于医疗保健的改善，预期寿命的增加，MD的频率显着增加，此时，同一年龄段的MDS的发病率（约为每100,000）高于慢性粒细胞性白血病（CML）或AML。驱动这种疾病的遗传事件尚不清楚，但是染色体条带3 Q26的转运是大约10％的MDS的反复出现的异常。该基因组位点含有EVI1，EVI1是一种基因，该基因在MDS中被染色体重排激活。 EVI1阳性的MDS患者会迅速发展为AML，其生存率不到一年。就特征MD的生物学机制而言，通常认为MDS细胞会损害分化和增加的凋亡。随着疾病的发展，细胞增加了失调的增殖和凋亡减少，保持不成熟，并且爆炸细胞的数量增加。缺乏再现MD的动物模型极大地限制了我们对这种疾病的理解。 我们小组的最新工作通过强迫EVI1在鼠骨髓（BM）细胞中的表达产生了重要的MDS动物模型。小鼠显示MDS的特征，包括高细胞BM，BM凋亡以及严重的细胞质和贫血。与患者中观察到的相反，EVI1呈现的鼠MDS并不能演变为AML，因此提供了一个独特的系统来在仍然可以治疗的阶段理解该疾病。使用该模型的初步研究给出了有关EVI1表达后立即影响红细胞生成，血小板形成和细胞循环的分子途径的明确线索凋亡，导致死亡。 具体目的旨在确定该进展的关键步骤，该步骤可用于阻止MDS的进步并遵循对MDS患者治疗的反应。它们包括鉴定在EVI1阳性BM细胞中破坏造血的分子途径（第一个目的）以及被EVI1激活或抑制的基因（第二目的）。第三个目标将集中在三氧化砷在治疗EVI1阳性MD的治疗中的作用以及抑制EVI1的小分子的分离。