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.

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）中发病率最高。MDS是一种复杂的疾病，其特征在于明显矛盾的共存特征。患者有红细胞生成不足和严重的全血细胞减少。同时，他们的BM是高细胞的，具有低原始细胞计数和三系分化。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）之前具有合理的长生存期。其他人只能通过输血来管理。一旦疾病进展为AML，预后差，生存期短。随着人口年龄的增长，MDS的发病率变得更加频繁，其在限制预期寿命方面的作用变得更加突出。MDS的遗传基础尚不清楚。由于骨髓细胞凋亡见于MDS，因此认为骨髓复制性衰老或不能对生长因子应答可能导致该疾病。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约10%的MDS中看到的染色体3带q26的重排。该区域包含EVI 1，该基因在正常BM中未检测到，但在MDS中通过重排被不适当地激活。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。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MDS小鼠模型，通过骨髓感染表达EVI 1的逆转录病毒并移植到同基因受体中。重建的小鼠总是死于具有MDS的几个特征的致命疾病，包括BM细胞过多、红细胞生成受损和贫血、血小板减少症、非常低的血细胞计数和造血器官中的细胞凋亡。用该模型的初步研究提供了关于受EVIL影响的造血和细胞循环途径的明确线索。这些作用在EVIL表达后立即发生在BM中。因为EVIL阳性小鼠在移植后10-12个月死亡，所以这些作用似乎不是致命的，这表明额外的事件必然不可逆地损害造血器官，导致死亡。MDS在这些小鼠中不会进展为AML。因此，这种模型是理想的，以了解疾病时，仍然是潜在的治疗。基于这些初步结果，我们提出，EVI 1的强制表达诱导小鼠的致命造血系统疾病，类似于人类MDS。该疾病从红细胞生成谱系受损的存活早期发展到造血细胞经历凋亡并且不响应生长因子的致命晚期。在这个阶段，血细胞计数急剧下降，出现多谱系缺陷，导致死亡。该提案的目标是进一步评估EVI 1在疾病中的作用，并了解第一阶段（存活）和第二阶段（致命）之间的过渡，旨在确定药物开发的合适靶点。我们计划使用分子生物学和体内系统的组合来剖析EVI 1的分子途径，并确定可用于开发新治疗方法的步骤。