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）：骨髓增生综合征（MDS）是一种致命的造血克隆疾病，老年人的发病率最高（> 60岁）。 MDS是一种复杂的疾病，其特征是显然是矛盾的共存特征。患者的红细胞生成不足和严重的全年减少症。同时，它们的BM是高细胞的，具有低爆炸计数和三利分化。一些患者会出现可以通过维持治疗来治疗的症状，并且在疾病的急性期（AML）之前具有相当长的生存率。其他人只能通过输血来管理。一旦该疾病发展到AML，预后就很差，生存期短。随着人口年龄的增加，MD的发生率变得更加频繁，并且其在限制预期寿命的作用变得更加突出。 MDS的遗传基础尚不清楚。由于MDS中可以看到BM凋亡，因此认为BM复制性衰老或无法应对生长因子可能有助于该疾病。第5和/或7染色体的部分缺失和丢失是MDS中的重复畸变，但被删除的基因仍然不明显。更具信息性的异常是在大约10％的MDS中看到的3染色体3带Q26的重排。该区域包含EVI1，EVI1是在正常BM中未检测到的基因，而是通过重排在MDS中不适当地激活的基因。 EVI1阳性的MDS患者会迅速发展为AML，其生存率不到一年。直到最近，还没有用于MD的细胞系或动物模型。因此，理解这种疾病和测试潜在治疗方面的进展非常慢。最近，我们通过表达EVI1的逆转录病毒并将其移植到合元受体中，开发了第一个通过骨髓感染的MDS模型。重建的小鼠总是屈服于致命疾病，该致命疾病具有MD的多种特征，包括BM超细胞性，红血病和贫血受损，血小板减少症，非常低的血液计数和造血器官的凋亡。通过该模型的初步研究为受邪恶影响的造血和细胞循环途径提供了明确的线索，这些影响在表达邪恶后立即发生在BM中，因为邪恶的阳性小鼠在移植后10-12个月屈服了，看来这些影响并不致命，这表明其他事件必须不可逆转地损害造成血肿的造成血肿的造成死亡。 MDS在这些小鼠中没有进展到AML。因此，该模型是理解在仍然可以治疗的情况下了解疾病的理想选择。基于这些初步结果，我们建议EVI1的强制表达诱导类似于人MD的小鼠的致命造血疾病。该疾病从可行的早期阶段发展，在该阶段中，促红细胞生成谱系受到损害，到致命的晚期造血细胞会发生凋亡，并且对生长因素没有反应。在此阶段，血液数量急剧下降，并且出现多段缺陷，导致死亡。该提案的目标是进一步评估EVI1在疾病中的作用，并了解第一个（可行）阶段与第二个（致命）阶段之间的过渡，目的是确定适合药物开发的目标。我们计划使用分子生物学和体内系统的组合来剖析EVI1的分子途径，并确定可用于开发新处理的步骤。