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
• 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: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7465550
• 关键词: A Mouse; Acute; Acute Myelocytic Leukemia; Affect; Age; Anemia; Animal Model; Animals; Apoptosis; Blast Cell; Blood; Blood Platelets; Blood Transfusion; Bone Marrow; Bone Marrow Transplantation; Cell Aging; Cell Cycle; Cell Line; Cells; Cessation of life; Characteristics; Chromosomes; Chromosomes, Human, Pair 3; Complex; Count; DNA Sequence Rearrangement; Defect; Development; Disease; Doctor of Philosophy; Drops; Dysmyelopoietic Syndromes; EVI1 gene; Erythroid; Erythropoiesis; Event; Genes; Genetic; Goals; Growth Factor; Hematopoietic; Human; Incidence; Infection; Life Expectancy; Maintenance Therapy; Modeling; Molecular; Molecular Biology; Mus; Myelogenous; Organ; Pancytopenia; Pathway interactions; Patients; Pharmacotherapy; Phase; Population; Qualifying; Research Personnel; Retroviridae; Role; Staging; Symptoms; System; Testing; Thinking; Thrombocytopenia; Time; Transplantation; base; chromosome 5 loss; drug development; exhaust; in vivo; mouse model; outcome forecast; progenitor; programs; reconstitution

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）中发病率最高。 MDS 是一种复杂的疾病，其特征是明显矛盾的共存特征。患者红细胞生成不足，全血细胞严重减少。同时，它们的骨髓细胞丰富，原始细胞计数低且三系分化。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）之前具有相当长的生存期。其他的只能通过输血来治疗。一旦病情进展为AML，预后较差，生存期短。随着人口年龄的增加，MDS的发病率越来越高，其限制预期寿命的作用也更加突出。 MDS 的遗传基础尚不清楚。由于骨髓增生异常综合征中可见骨髓细胞凋亡，因此认为骨髓复制衰老或无法对生长因子做出反应可能导致该疾病。 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，但被删除的基因仍未被识别。信息量更大的异常是约 10% 的 MDS 中出现的 3 号染色体带 q26 重排。该区域包含 EVI1，这是一种在正常 BM 中未检测到的基因，但在 MDS 中通过重排被不适当地激活。 EVI1 阳性 MDS 患者会出现致命的造血缺陷，并迅速发展为 AML，一般来说，他们的生存期不到一年。直到最近，还没有针对 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极其缓慢。最近，我们通过用表达 EVI1 的逆转录病毒进行骨髓感染并移植到同基因受体中，开发了第一个 MDS 小鼠模型。重组后的小鼠总是会死于具有MDS多种特征的致命疾病，包括骨髓细胞增多、红细胞生成受损和贫血、血小板减少、血细胞计数极低以及造血器官凋亡。使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。这些效应在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，所以这些效应似乎不是致命的，表明额外的事件必定不可逆地损害造血器官导致死亡。这些小鼠中的 MDS 不会进展为 AML。因此，该模型非常适合了解仍有可能治愈的疾病。基于这些初步结果，我们提出，EVI1 的强制表达会在小鼠中诱导一种类似于人类 MDS 的致命造血系统疾病。该疾病从红细胞生成谱系受损的可行早期阶段发展到造血细胞凋亡且对生长因子不产生反应的致命晚期阶段。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 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，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疗法的步骤。