Flexible and Somatic Mouse Models for Myelodysplastic Syndrome Progression

描述（由申请人提供）：骨髓增生异常综合征（MDS）是目前最常见于老年人的无法治愈的白血病前期疾病，在美国每年约有14000例新病例。这些病例中约有30-40%进展为急性髓性白血病（AML）。由于迫切需要改善这一群体的治疗，因此建立有效的建模系统（包括小鼠模型）来研究MDS和AML中常见的遗传病变至关重要。然而，遗传变化诱导MDS向AML进展的精确分子机制仍然知之甚少。本研究的重点是建立一种创新的小鼠模型，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体内，研究MDS的进展和AML的转化。这些小鼠已经被改造成携带逆转录病毒受体TVA，特别是在表达致癌基因SALL4B的造血干细胞中。我们最近发现了这种新的致癌基因，并发现SALLB的过表达在2个月大的小鼠中表现为MDS，随后表现为具有长潜伏期的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，从而导致SALL4B癌基因介导MDS向AML的转化。为了验证我们的假设，我们将RAS编码的逆转录病毒传递到SALL4B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SALL4B癌基因之间的协同作用。拟议的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。我们对这种创新小鼠模型的研究的一个重要成果是有可能开发有效的MDS靶向治疗方法，从而改善面临这种不治之症的患者的预后。这一进展通过降低与MDS相关的高死亡率，为公共卫生带来了重大益处。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无法治愈的白血病前期疾病，在美国每年约有14000例新病例。这些病例中约有30-40%进展为急性髓性白血病（AML）。由于迫切需要改善这一群体的治疗，因此建立有效的建模系统（包括小鼠模型）来研究MDS和AML中常见的遗传病变至关重要。然而，遗传变化诱导MDS向AML进展的精确分子机制仍然知之甚少。本研究的重点是建立一种创新的小鼠模型来研究MDS的进展和AML的转化。我们对这种创新小鼠模型的研究的一个重要成果是有可能开发有效的MDS靶向治疗方法，从而改善面临这种不治之症的患者的预后。这一进展通过降低与MDS相关的高死亡率，为公共卫生带来了重大益处。

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.