Flexible and Somatic Mouse Models for Myelodysplastic Syndrome Progression

描述(申请人提供)：骨髓增生异常综合征(MDS)是目前最常见的不可治愈的白血病前期疾病，在美国每年约有14,000例新病例。其中约30-40%进展为急性髓系白血病(AML)。随着这一群体迫切需要改进治疗，关键是要建立有效的建模系统(包括小鼠模型)来研究MDS和AML中常见的遗传损害。然而，基因改变导致MDS进展为AML的确切分子机制仍然知之甚少。这项拟议的研究集中在一种创新的小鼠模型上，通过将编码高活性KRAS和NRAS的禽类逆转录病毒体细胞递送到转基因小鼠，以研究MDS的进展和AML转化。这些小鼠被改造成携带逆转录病毒受体TVA，特别是在表达癌基因SALL4B的造血干细胞中。我们最近发现了这个新的癌基因，并发现在两个月大的小鼠中过表达SALLB会出现MDS，随后表现出长时间的AML转化。我们假设，需要额外的突变来激活增殖途径，如RAS基因信号通路，使SALL4B癌基因介导MDS向AML的转化。为了验证我们的假设，编码RAS的逆转录病毒将被输送到SALL4B癌基因过度表达的小鼠骨髓中。通过我们的小鼠模型，我们将表征过度活跃的RAS与SALL4B癌基因之间的协同作用。这些研究将促进我们对与MDS进展和AML转化相关的分子事件的理解。我们用这种创新的小鼠模型进行研究的一个重要结果是，有可能为MDS开发有效的靶向治疗，从而改善面临这种不治之症的患者的预后。这一进步通过降低与MDS相关的高死亡率，为公共卫生带来了重大好处。公共卫生相关性：目前，骨髓增生异常综合征(MDS)是一种不可治愈的白血病前期疾病，最常发生在老年人中，在美国每年约有14,000例新病例。其中约30-40%进展为急性髓系白血病(AML)。随着这一群体迫切需要改进治疗，关键是要建立有效的建模系统(包括小鼠模型)来研究MDS和AML中常见的遗传损害。然而，基因改变导致MDS进展为AML的确切分子机制仍然知之甚少。建议的研究集中在一种创新的小鼠模型上，用于研究MDS进展和AML转化。我们用这种创新的小鼠模型进行研究的一个重要结果是，有可能为MDS开发有效的靶向治疗，从而改善面临这种不治之症的患者的预后。这一进步通过降低与MDS相关的高死亡率，为公共卫生带来了重大好处。

DESCRIPTION (provided by applicant): Myelodysplastic syndrome (MDS) is, at present, incurable preleukemic disease occurring most frequently among the elderly with about 14,000 new cases per year in the USA. About 30-40% of these cases progress to acute myeloid leukemia (AML). With an urgent need to improve therapy in this group, it is critical to generate effective modeling systems (including mouse models) for investigating the genetic lesions commonly observed in MDS and AML. However, the precise molecular mechanisms whereby genetic changes induce the progression of MDS to AML remain poorly understood. The proposed research focuses on an innovative mouse model for studying MDS progression and AML transformation through the somatic delivery of avian retroviruses that encode hyperactive KRAS and NRAS to transgenic mice. These mice have been engineered to bear the retroviral receptor, TVA, specifically within the hematopoietic stem cells that express an oncogene, SALL4B. We recently have identified this new oncogene and have discovered that overexpression of SALLB in mice exhibits MDS at age two months and, subsequently, displays AML transformation with a long latency. We hypothesize that additional mutations are required to activate a proliferative pathway, such as the RAS gene signaling pathway, to cause the SALL4B oncogene to mediate the transformation of MDS to AML. To test our hypothesis, RAS- encoding retroviruses will be delivered to mouse bone marrow where the SALL4B oncogene is overexpressed. Through our mouse model, we will characterize the cooperativity between hyperactive RAS with the SALL4B oncogene. The proposed studies will advance our understanding of the molecular events associated with MDS progression and AML transformation. An important outcome of our research with this innovative mouse model lies in the potential for developing effective target therapies for MDS thus improving the prognosis for patients facing this incurable disease. Such an advancement presents significant benefits to public health by reducing the high rate of mortality associated with MDS. PUBLIC HEALTH RELEVANCE: Myelodysplastic syndrome (MDS) is, at present, incurable preleukemic disease occurring most frequently among the elderly with about 14,000 new cases per year in the USA. About 30-40% of these cases progress to acute myeloid leukemia (AML). With an urgent need to improve therapy in this group, it is critical to generate effective modeling systems (including mouse models) for investigating the genetic lesions commonly observed in MDS and AML. However, the precise molecular mechanisms whereby genetic changes induce the progression of MDS to AML remain poorly understood. The proposed research focuses on an innovative mouse model for studying MDS progression and AML transformation. An important outcome of our research with this innovative mouse model lies in the potential for developing effective target therapies for MDS thus improving the prognosis for patients facing this incurable disease. Such an advancement presents significant benefits to public health by reducing the high rate of mortality associated with MDS.