Inactivating EVI1 for the Treatment of Myelodysplastic *

灭活 EVI1 用于治疗骨髓增生异常*

基本信息

  • 批准号:
    7022781
  • 负责人:
  • 金额:
    $ 38.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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(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,并且在血液恶性肿瘤中具有高的年发病率,每年诊断出约14,000例新病例。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。随着预期寿命的增加,由于医疗保健的改善,MDS的频率显著增加,此时MDS的发病率(约5/100,000)高于相同年龄组的慢性髓性白血病(CML)或AML。驱动这种疾病的遗传事件尚不清楚,但是染色体带3 q26易位是在约10%的MDS中观察到的复发性异常。该基因组位点包含EVI 1,一种在MDS中通过染色体重排不适当激活的基因。EVI 1阳性MDS患者发生致命的造血缺陷,迅速演变为AML,通常其生存期不到一年。就表征MDS的生物学机制而言,通常认为MDS细胞具有受损的分化和增加的凋亡。随着疾病的发展,细胞的增殖失调增加,凋亡减少,保持不成熟,原始细胞的数量增加。缺乏一个动物模型,再现MDS强烈限制了我们对这种疾病的理解。 我们小组最近的工作通过迫使小鼠骨髓(BM)细胞中EVI 1的表达产生了一个重要的MDS动物模型。小鼠表现出MDS的特征,包括骨髓细胞过多、骨髓细胞凋亡、严重的血细胞减少和贫血。与在患者中观察到的相反,EVI 1-敏感性鼠MDS不会演变为AML,因此提供了一个独特的系统来了解仍有可能治疗的阶段的疾病。使用该模型的初步研究已经给出了关于在EVI 1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,并且表明在EVI 1阳性小鼠中,疾病从红细胞生成谱系受损的存活早期阶段进展到以贫血、细胞凋亡、严重血细胞减少、BM细胞凋亡为特征的总是致命的晚期阶段,导致死亡。 具体目标旨在确定该进展中的关键步骤,这些步骤可用于阻止MDS的进展并跟踪MDS患者对治疗的反应。它们包括鉴定破坏EVI 1阳性BM细胞中造血的分子途径(第一个目标)和被EVI 1激活或抑制的基因(第二个目标)。第三个目标将集中在三氧化二砷在治疗EVI 1阳性MDS中的作用和抑制EVI 1的小分子的分离上。

项目成果

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Giuseppina Nucifora其他文献

Giuseppina Nucifora的其他文献

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{{ truncateString('Giuseppina Nucifora', 18)}}的其他基金

A Mouse Model of Myelodysplastic Syndrome Progression
骨髓增生异常综合征进展的小鼠模型
  • 批准号:
    7465550
  • 财政年份:
    2005
  • 资助金额:
    $ 38.75万
  • 项目类别:
Inactivating EVI1 for the Treatment of Myelodysplastic *
灭活 EVI1 用于治疗骨髓增生异常 *
  • 批准号:
    7487814
  • 财政年份:
    2005
  • 资助金额:
    $ 38.75万
  • 项目类别:
Inactivating EVI1 for the Treatment of Myelodysplastic *
灭活 EVI1 用于治疗骨髓增生异常 *
  • 批准号:
    7278665
  • 财政年份:
    2005
  • 资助金额:
    $ 38.75万
  • 项目类别:
A Mouse Model of Myelodysplastic Syndrome Progression
骨髓增生异常综合征进展的小鼠模型
  • 批准号:
    7650235
  • 财政年份:
    2005
  • 资助金额:
    $ 38.75万
  • 项目类别:
Inactivating EVI1 for the Treatment of Myelodysplastic *
灭活 EVI1 用于治疗骨髓增生异常 *
  • 批准号:
    7128100
  • 财政年份:
    2005
  • 资助金额:
    $ 38.75万
  • 项目类别:
A Mouse Model of Myelodysplastic Syndrome Progression
骨髓增生异常综合征进展的小鼠模型
  • 批准号:
    7082227
  • 财政年份:
    2005
  • 资助金额:
    $ 38.75万
  • 项目类别:
A Mouse Model of Myelodysplastic Syndrome Progression
骨髓增生异常综合征进展的小鼠模型
  • 批准号:
    6984724
  • 财政年份:
    2005
  • 资助金额:
    $ 38.75万
  • 项目类别:
A Mouse Model of Myelodysplastic Syndrome Progression
骨髓增生异常综合征进展的小鼠模型
  • 批准号:
    7261916
  • 财政年份:
    2005
  • 资助金额:
    $ 38.75万
  • 项目类别:
EVI1 Expression is a Prognostic Marker of CML
EVI1 表达是 CML 的预后标志物
  • 批准号:
    6750118
  • 财政年份:
    2003
  • 资助金额:
    $ 38.75万
  • 项目类别:
EVI1 Expression is a Prognostic Marker of CML
EVI1 表达是 CML 的预后标志物
  • 批准号:
    6610092
  • 财政年份:
    2003
  • 资助金额:
    $ 38.75万
  • 项目类别:

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