Genetic Modifiers for Cancer Stem Cells in Secondary MDS/AML

描述（由申请人提供）：为什么有些人得了癌症，而另一些人却得不到癌症生物学的核心。 最近，NCI邀请了领先的癌症研究人员来确定将改变我们对癌症的理解和治疗的挑衅性问题。 我们的应用程序解决了这些问题之一：是否有可定义的性质的癌前病变，预测进展的可能性。 这不仅具有深刻的生物学意义，而且与癌症易感性的人也有很大的相关性。 患有先天性骨髓衰竭综合征（例如范可尼贫血、Shwachman-Diamond综合征、重度先天性神经退行性疾病和先天性角化不良）的患者发生危及生命的急性髓性白血病/骨髓增生异常综合征（AML/MDS）的风险大大增加（1000倍）。 导致疾病进展的遗传因素有哪些？ 这种进展是否可以首先通过鉴定这些遗传共同修饰剂来预防，然后设计预防措施？ 该提案旨在确定Shwachman-Diamond综合征患者中出现的遗传共同修饰物，Shwachman-Diamond综合征是一种更常见的遗传性骨髓衰竭综合征，具有AML/MDS的风险。 然而，两个主要障碍阻碍进展：疾病的低患病率和长达十年的潜伏期。 为了克服这些障碍，我们正在开发一种成年斑马鱼Shwachman-Diamond综合征模型，并筛选导致白血病的基因突变。 该疾病是由于SBDS基因突变引起的，该基因编码一种参与核糖体成熟的蛋白质。 我们已经克隆了高度同源的斑马鱼基因，sbds，其启动子的sbds基因，并已开发工具的控制表达的Sbds。 有趣的是，几乎所有患有这种综合征的白血病患者都会丢失7号染色体。 这种异常也见于许多儿童和成人AML/MDS患者。 虽然在染色体7 q上有一个最小缺失区域，但该肿瘤抑制基因的身份尚不清楚。 我们将在我们的模型系统中测试几个候选基因。 通过鉴定遗传共同修饰物并确定它们如何干扰造血，我们最终将能够为那些已经发展为AML/MDS的人设计预防策略以及更有效的治疗方法。 此外，由于Shwachman-Diamond综合征也会导致胰腺功能不全，生长迟缓和发育障碍，我们的模型将为其他生物学家和临床医生增加价值。

DESCRIPTION (provided by applicant): Why do some people get cancer and others do not gets to the heart of cancer biology. Recently, the NCI invited leading cancer investigators to identify provocative questions that will transform our understanding and treatment of cancer. Our application addresses one of these questions: are there definable properties of premalignant lesions that predict the likelihood of progression. This is not just of profound biological importance, but also of great relevance to people with cancer predisposition. Patients with congenital bone marrow failure syndromes (for example, Fanconi anemia, Shwachman-Diamond Syndrome, Severe Congenital Neuropenia, and dyskeratosis congenital) are at greatly increased risk (1000x) for developing life-threatening acute myeloid leukemia/myelodysplastic syndromes (AML/MDS). What are the genetic factors that contribute to disease progression? Can this progression be prevented first by identification of these genetic co-modifiers and then to design preventative measures? This proposal seeks to identify genetic co-modifiers that arise in patients with Shwachman-Diamond Syndrome, one of the more common inherited bone marrow failure syndromes with the risk of AML/MDS. However, two major obstacles block progression: the low prevalence of the disease and the decade long latency period. To overcome these obstacles we are developing an adult zebrafish model of Shwachman-Diamond Syndrome and screen for genetic mutations that result in leukemia. The disease is due to a mutation in the SBDS gene, which encodes a protein involved in ribosomal maturation. We have cloned the highly homologous zebrafish gene, sbds, and its promoter for the sbds gene and have developed tools for controlled expressions of Sbds. Fascinatingly, almost all patients with this syndrome who develop leukemia acquire loss of chromosome 7. This abnormality is also found in a number of pediatric and adult patients with AML/MDS. While there is a minimally deleted region on chromosome 7q, the identity of that tumor suppressor is unknown. We will test several candidate genes in our model system. By identifying genetic co-modifiers and determining how they disturb hematopoiesis, we will be able to eventually design preventative strategies as well as more effective therapies for those who have already developed AML/MDS. In addition, since Shwachman-Diamond Syndrome also causes pancreatic insufficiency, growth retardation, and developmental disabilities, our model will have added value to other biologists and clinicians.