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
• 负责人: Giuseppina Nucifora
• 金额: $ 38.75万
• 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: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6984724
• 关键词: acute myelogenous leukemia; bone marrow disorder; cell differentiation; cell growth regulation; cell senescence; developmental genetics; disease /disorder model; dyserythropoietic anemia; gene mutation; gene rearrangement; genetic regulation; hematopoiesis; hematopoietic stem cells; human tissue; laboratory mouse; neoplasm /cancer genetics; pathologic process; preneoplastic state

DESCRIPTION (provided by applicant): Myelodysplastic syndrome (MDS) is a fatal hematopoietic clonal disorder with the highest incidence among older people (>60 years). MDS is a complex disease characterized by apparently contradictory coexisting features. The patients have insufficient erythropoiesis and severe pancytopenia. At the same time, their BM is hypercellular with low blast counts and trilineage differentiation. Some patients develop symptoms that can be managed with maintenance therapy and have reasonably long survival before progressing to the acute phase (AML) of the disease. Others can be managed only with blood transfusions. Once the disease progresses to AML, the prognosis is poor with short survival. As the age of the population increases, the incidence of MDS becomes more frequent and its role in limiting life expectancy becomes more prominent. The genetic bases of MDS are not known. Because BM apoptosis is seen in MDS, it is thought that BM replicative senescence or inability to respond to growth factors could contribute to the disease. Partial deletion and loss of chromosome 5 and/or 7 are recurring aberrations in MDS but the genes that are deleted remain unidentified. A more informative abnormality is the rearrangement of chromosome 3 band q26 seen in about 10% of MDS. This region contains EVI1, a gene not detected in normal BM but inappropriately activated in MDS by the rearrangement. EVI1-positive MDS patients develop fatal hematopoietic defects rapidly evolving to AML and in general their survival is less than one year. Until very recently, there was no cell line or animal model for MDS. Therefore, the progress in understanding this disease and testing potential treatments has been extremely slow. Very recently, we have developed the first murine model of MDS by bone marrow infection with an EVI1-expressing retrovirus and transplantation into syngeneic recipients. The reconstituted mice invariably succumb to a fatal disease that has several characteristics of MDS, including BM hypercellularity, impaired erythropoiesis and anemia, thrombocytopenia, very low blood counts, and apoptosis in hematopoietic organs. Preliminary studies with this model have provided clear clues about hematopoietic and cell cycling pathways affected by EVIL These effects occur in BM immediately after expression of EVIL Because the EVIl-positive mice succumb 10-12 months after transplantation, it appears that these effects are not fatal, suggesting that additional events must irreversibly damage the hematopoietic organs leading to death. MDS does not progress to AML in these mice. Therefore this model is ideal to understand the disease when is still potentially treatable. Based on these preliminary results, we propose that the forced expression of EVI1 induces a fatal hematopoietic disease in mice that resembles human MDS. The disease progresses from a viable early stage in which the erythropoietic lineage is compromised, to a fatal late stage in which hematopoietic cells undergo apoptosis and do not respond to growth factors. In this stage, blood counts sharply drop, and multi-lineage defects appear, leading to death. The goals of this proposal are to further evaluate the role of EVI1 in the disease and understand the transition between the first (viable) stage and the second (fatal) stage, with the intent of identifying suitable targets for drugs development. We plan to use a combination of molecular biology and in vivo systems to dissect the molecular pathways of EVI1 and identify steps that can be used for the development of new treatments.

描述（由申请人提供）：骨髓增生异常综合征（MDS）是一种致命的造血克隆性疾病，在老年人（60岁以下）中发病率最高。MDS是一种具有明显矛盾共存特征的复杂疾病。患者红细胞生成能力不足，全血细胞减少严重。同时，他们的骨髓是高细胞的，低细胞计数和三龄分化。一些患者出现的症状可以通过维持治疗来控制，并且在进展到疾病的急性期（AML）之前有相当长的生存期。其他的只能通过输血来控制。一旦病情发展为急性髓性白血病，预后差，生存期短。随着人口年龄的增长，MDS的发病率越来越高，其限制预期寿命的作用也越来越突出。MDS的遗传基础尚不清楚。由于骨髓细胞凋亡在MDS中可见，因此人们认为骨髓细胞复制性衰老或对生长因子无反应可能是导致该疾病的原因。5号和/或7号染色体的部分缺失和丢失是MDS中反复出现的畸变，但缺失的基因仍未确定。一个更有意义的异常是在大约10%的MDS中看到的3号染色体q26带重排。该区域包含EVI1，这是一个在正常BM中未检测到的基因，但在MDS中被重排不当激活。evi1阳性MDS患者会发展为致命的造血缺陷，并迅速发展为AML，通常他们的生存期不到一年。直到最近，还没有MDS的细胞系或动物模型。因此，了解这种疾病和测试潜在治疗方法的进展非常缓慢。最近，我们开发了第一个通过骨髓感染表达evi1的逆转录病毒并移植到同基因受体的MDS小鼠模型。重组后的小鼠总是死于一种致命的疾病，这种疾病具有MDS的几个特征，包括骨髓细胞增多、红细胞功能受损和贫血、血小板减少、血细胞计数极低和造血器官凋亡。该模型的初步研究已经为EVIL影响造血和细胞循环途径提供了清晰的线索。这些影响在EVIL表达后立即发生在骨髓中。由于EVIL阳性小鼠在移植后10-12个月死亡，这些影响似乎不是致命的，这表明其他事件必须对造血器官造成不可逆的损害，从而导致死亡。在这些小鼠中，MDS不会进展为AML。因此，该模型对于了解仍有可能治疗的疾病是理想的。基于这些初步结果，我们提出EVI1的强制表达在小鼠中诱导了一种类似于人类MDS的致命造血疾病。该疾病从红细胞生成谱系受损的可存活早期发展到造血细胞凋亡和对生长因子无反应的致命晚期。在这个阶段，血液计数急剧下降，出现多谱系缺陷，导致死亡。该提案的目标是进一步评估EVI1在疾病中的作用，并了解第一（可存活）阶段和第二（致命）阶段之间的过渡，旨在确定药物开发的合适靶点。我们计划结合分子生物学和体内系统来剖析EVI1的分子途径，并确定可用于开发新治疗方法的步骤。