A model of myelodysplastic syndrome progression and leukemic stem cells

描述（由申请人提供）：骨髓增生异常综合征（MDS）是最常见于老年患者的干细胞恶性肿瘤，导致每年约14，000例新发病例的高发病率。MDS的发病率随着我们人口的老龄化而持续增加。约30-40%的MDS病例进展为急性髓系白血病（AML），预后不良。从正常健康到MDS再到急性白血病的进展中发生的事件顺序未知。我们发现了一种新的癌基因SALL 4 B，它在人类白血病细胞系和几乎100%的原代AML细胞中组成型表达。我们已经表明过表达SALL 4 B的转基因小鼠表现出MDS样特征，并且随后表现出与粒细胞/巨噬细胞祖细胞（GMP）和造血干细胞（HSC）的选择性扩增相关的AML转化。这一提议的假设有两个研究组成部分。首先，我们推测SALL 4 B的异常表达通过激活Bmi-1使HSC/HPC永生化。其次，我们推测SALL 4 B与RAS协同作用，并通过增强HSC/HPC的增殖促进MDS向AML的进展。为了验证我们的假设，我们提出了三个具体但互补的目标，旨在深入分析我们的SALL 4 B小鼠模型，并阐明MDS和AML的发展。具体目标1侧重于确定导致与MDS和AML转化发展相关的SALL 4 B-HSC/GMP扩增的机制。具体目标2侧重于鉴定介导MDS进展的分子途径。具体目标3侧重于SALLB与MDS进展中的第二突变的合作。我们的新型小鼠模型是研究这些疾病和深入了解MDS向致命性晚期AML进展的理想模型。涉及MDS和MDS转化的致癌事件的顺序和时间尚不清楚，这是我们目前对这些疾病了解的一个重大不足。我们的方法是创新的，因为它包含了一个新发现的癌基因和一个新的小鼠模型的作用。重要的是，我们期望扩大围绕MDS和MDS转化的知识体系，从而导致识别用于治疗和干预的新的治疗靶点。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。我们还将把这些研究转化为新的诊断和预后工具，用于预测那些疾病可能进展为AML的患者，AML通常对患者是致命的。

DESCRIPTION (provided by applicant): Myelodysplastic syndromes (MDS) are stem-cell malignancies most frequently seen among elderly patients, resulting in a high annual incidence of approximately 14,000 new cases per year. The incidence of MDS continues to increase as our population ages. About 30-40% of MDS cases progress to acute myeloid leukemia (AML) with poor prognosis. The order of events occurring in the progression from normal health to MDS to acute leukemia is unknown. We have discovered a new oncogene, SALL4B, which is expressed constitutively in human leukemia cell lines and in almost 100% of primary AML cells. We have shown that transgenic mice that overexpress SALL4B exhibit MDS- like features and, subsequently, AML transformation associated with selective expansion of granulocyte/macrophage progenitor cells (GMPs) and hematopoetic stem cells (HSCs). The hypothesis underlying this proposal has two research components. First, we theorize that aberrant expression of SALL4B immortalizes HSCs/HPCs through activation of Bmi-1. Second, we theorize that SALL4B acts in concert with RAS and promotes progression of MDS to AML by enhancing proliferation of HSCs/HPCs. To test our hypothesis, we are proposing three specific but complementary aims designed to permit in-depth analysis of our SALL4B mouse model and to illuminate the development of MDS and AML. Specific Aim 1 focuses on determination of mechanisms leading to expansion of SALL4B-HSC/GMP associated with development of MDS and AML transformation. Specific Aim 2 focuses on identification of the molecular pathway(s) that mediates MDS progression. Specific Aim 3 focuses on cooperation of SALLB with second mutations in MDS progression. Our novel mouse model is ideal for investigating these diseases and gaining insight in the progression of MDS to fatal, late stage AML. The order and timing of oncogenic events involving MDS and MDS transformation are unknown and this is a major shortfall in our current understanding of these diseases. Our approach is innovative because it encompasses the role of a newly identified oncogene and a novel mouse model. Importantly, we expect to expand the body of knowledge surrounding MDS and MDS transformation consequently leading to the identification of novel therapeutic targets for treatment and intervention. 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. We will also translate these studies into new diagnostic and prognostic tools for predicting those patients whose disease may progress to AML, which is most generally lethal to the patient.