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）是目前最常见于老年人的一种无法治愈的白血病前期疾病，在美国每年约有14，000例新病例。这些病例中约30-40%进展为急性髓性白血病（AML）。由于迫切需要改善这一组的治疗，因此产生有效的建模系统（包括小鼠模型）以研究MDS和AML中常见的遗传病变至关重要。然而，遗传变化诱导MDS向AML进展的确切分子机制仍知之甚少。拟议的研究重点是一种创新的小鼠模型，用于研究MDS进展和AML转化，通过向转基因小鼠体细胞递送编码高度活跃的KRAS和NRAS的禽类逆转录病毒。这些小鼠被设计成携带逆转录病毒受体TVA，特别是在表达癌基因SALL 4 B的造血干细胞内。我们最近已经确定了这种新的癌基因，并发现小鼠中SALLB的过度表达在两个月大时表现出MDS，随后表现出AML转化，潜伏期较长。我们假设需要额外的突变来激活增殖途径，如RAS基因信号传导途径，从而导致SALL 4 B癌基因介导MDS向AML的转化。为了验证我们的假设，编码RAS的逆转录病毒将被递送到SALL 4 B癌基因过表达的小鼠骨髓中。通过我们的小鼠模型，我们将描述过度活跃的RAS与SALL 4 B癌基因之间的协同性。拟议的研究将促进我们对MDS进展和AML转化相关分子事件的理解。我们对这种创新小鼠模型的研究的一个重要成果在于开发有效的MDS靶向疗法的潜力，从而改善面临这种不治之症的患者的预后。这种进步通过降低与MDS相关的高死亡率而对公共卫生带来显著益处。公共卫生相关性：骨髓增生异常综合征（MDS）是目前最常见于老年人的不可治愈的白血病前期疾病，在美国每年约有14，000例新发病例。这些病例中约30-40%进展为急性髓性白血病（AML）。由于迫切需要改善这一组的治疗，因此产生有效的建模系统（包括小鼠模型）以研究MDS和AML中常见的遗传病变至关重要。然而，遗传变化诱导MDS向AML进展的确切分子机制仍知之甚少。拟议的研究重点是研究MDS进展和AML转化的创新小鼠模型。我们对这种创新小鼠模型的研究的一个重要成果在于开发有效的MDS靶向疗法的潜力，从而改善面临这种不治之症的患者的预后。这种进步通过降低与MDS相关的高死亡率而对公共卫生带来显著益处。

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.