Genetic Modifiers for Cancer Stem Cells in Secondary MDS/AML

继发性 MDS/AML 中癌症干细胞的基因修饰

• 批准号: 8787717
• 负责人: Seth Joel Corey
• 金额: $ 16.88万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787717
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Allogenic; Biological; Biological Models; Blood; Cancer Biology; Candidate Disease Gene; Childhood; Chromosomes; Chromosomes, Human, Pair 7; Communities; Cues; DNA Sequence Alteration; Development; Developmental Disabilities; Diagnosis; Diamond; Disease; Disease Progression; Down-Regulation; Dyskeratosis Congenita; Dysmyelopoietic Syndromes; Endothelial Cells; Exocrine pancreatic insufficiency; Fanconi' s Anemia; Fibroblasts; Functional disorder; Genes; Genetic; Genetic Screening; Goals; Growth; Health; Heart; Hematopoiesis; Hematopoietic; Human; Human Chromosomes; Inborn Genetic Diseases; Incidence; Inherited; Lead; Lesion; Life; Loss of Heterozygosity; Low Prevalence; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Modeling; Morbidity - disease rate; Mutation; Myelopoiesis; Neutropenia; Osteoblasts; Pancreas; Patients; Play; Preclinical Drug Evaluation; Predisposition; Premalignant; Process; Property; Proteins; Regimen; Research Personnel; Risk; Role; Secondary Myelodysplastic Syndrome; Secondary to; Skeletal Development; Stem cell transplant; Stem cells; Stromal Cells; Syndrome; Testing; Toxic effect; Transgenes; Transgenic Organisms; Transplantation; Tumor Suppressor Genes; Tumor Suppressor Proteins; Validation; Zebrafish; aging population; bone marrow failure syndrome; cancer stem cell; cancer therapy; chromosome 7 loss; cofactor; design; effective therapy; improved; insight; leukemia; leukemogenesis; mortality; novel; overexpression; prevent; promoter; tool

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.

描述（由申请人提供）：为什么有些人会患癌症，而另一些人却没有触及癌症生物学的核心。 最近，美国国家癌症研究所邀请领先的癌症研究人员来确定一些具有挑战性的问题，这些问题将改变我们对癌症的理解和治疗。 我们的应用解决了以下问题之一：癌前病变是否存在可预测进展可能性的可定义特性。 这不仅具有深远的生物学意义，而且与患有癌症的人也有很大关系。 先天性骨髓衰竭综合征（例如范可尼贫血、Shwachman-Diamond 综合征、严重先天性神经减少症和先天性角化不良）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？ 是否可以首先通过识别这些遗传辅助修饰物然后设计预防措施来阻止这种进展？ 该提案旨在识别 Shwachman-Diamond 综合征患者中出现的遗传共修饰因子，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 风险。 然而，有两个主要障碍阻碍了进展：该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Shwachman-Diamond 综合征的成年斑马鱼模型，并筛选导致白血病的基因突变。 这种疾病是由 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。 我们克隆了高度同源的斑马鱼基因 sbds 及其 sbds 基因的启动子，并开发了用于控制 Sbds 表达的工具。 令人着迷的是，几乎所有患有这种综合征的白血病患者都会出现 7 号染色体缺失。这种异常现象也见于一些患有 AML/MDS 的儿童和成人患者。 虽然 7q 染色体上有一个最小缺失区域，但该肿瘤抑制因子的身份尚不清楚。 我们将在我们的模型系统中测试几个候选基因。 通过识别遗传辅助修饰因子并确定它们如何干扰造血功能，我们最终将能够为那些已经患有 AML/MDS 的患者设计预防策略以及更有效的治疗方法。 此外，由于Shwachman-Diamond综合征还会导致胰腺功能不全、生长迟缓和发育障碍，因此我们的模型将为其他生物学家和临床医生带来附加值。