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
• 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: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082227
• 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(&gt；60岁)中发病率最高。MDS是一种复杂的疾病，其特征是明显相互矛盾的共存特征。患者红细胞生成不足，全血细胞减少严重。同时，它们的骨髓是高细胞的，原始细胞计数低，三线分化。一些患者出现可以通过维持治疗控制的症状，并在发展到疾病的急性期(AML)之前有相当长的存活时间。其他的只能通过输血来治疗。一旦进展到AML，预后差，生存时间短。随着人口年龄的增加，MDS的发病率变得更加频繁，其在限制预期寿命方面的作用也更加突出。MDS的遗传基础尚不清楚。由于骨髓细胞凋亡在MDS中可见，因此认为骨髓复制性衰老或对生长因子无反应可能与该病有关。5号和/或7号染色体的部分缺失和丢失是MDS中反复出现的异常，但缺失的基因仍未确定。一个更能提供信息的异常是染色体3带Q26的重排，在大约10%的MDS中可见。该区域包含EVI1，这是一种在正常骨髓中未检测到的基因，但在MDS中通过重排而被不适当地激活。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。直到最近，还没有MDS的细胞系或动物模型。因此，在了解这种疾病和测试可能的治疗方法方面的进展极其缓慢。最近，我们建立了第一个通过骨髓感染表达EVI1逆转录病毒并移植到同基因受体的MDS小鼠模型。重组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，包括骨髓高细胞增多，红细胞生成受损和贫血，血小板减少，血细胞计数非常低，以及造血器官的细胞凋亡。对这个模型的初步研究已经提供了受邪恶影响的造血和细胞循环途径的明确线索。这些影响发生在邪恶表达后立即发生在骨髓中，因为邪恶阳性的小鼠在移植后10-12个月死亡，似乎这些影响不是致命的，这表明额外的事件肯定会不可逆转地损害造血器官导致死亡。在这些小鼠中，MDS不会进展为AML。因此，当疾病仍有可能治愈时，这个模型是了解这种疾病的理想选择。基于这些初步结果，我们推测EVI1的强制表达在小鼠中诱导了一种类似于人类MDS的致命的造血疾病。这种疾病从红系受损的存活早期进展到致命的晚期，造血细胞发生凋亡，对生长因子没有反应。在这一阶段，血细胞数量急剧下降，出现多谱系缺陷，导致死亡。这项建议的目标是进一步评估EVI1在疾病中的作用，并了解第一(存活)阶段和第二(致命)阶段之间的过渡，目的是为药物开发确定合适的靶点。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。