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）：为什么有些人患癌症而另一些人没有成为癌症生物学的核心。 最近，NCI邀请领先的癌症研究者确定挑衅性问题，以改变我们对癌症的理解和治疗。 我们的应用程序解决了以下问题之一：是否存在预测前期病变的可确定特性，以预测进展的可能性。 这不仅具有深远的生物学重要性，而且与癌症患者易感性相关。 先天性骨髓衰竭综合征的患者（例如，法科尼贫血，Shwachman-Diamond综合征，严重的先天性神经乳腺癌和异性疾病先天性疾病）的风险大大增加（1000 x），用于发展生命的急性肌细胞性白血病/肌动物症/肌瘤异常综合征（amm-h/mds）。 有助于疾病进展的遗传因素是什么？ 是否可以通过鉴定这些遗传共同修饰者，然后设计预防措施来首先防止这种进展？ 该建议旨在确定Shwachman-Diamond综合征患者中出现的遗传共塑剂，Shwachman-Diamond综合征是具有AML/MDS风险的最常见遗传性骨髓衰竭综合症之一。 但是，两个主要的障碍阻碍了进展：疾病的低患病率和长期的潜伏期。 为了克服这些障碍，我们正在开发一种成年斑马鱼模型的Shwachman-Diamond综合征和筛查遗传突变，导致白血病。 该疾病是由于SBDS基因的突变引起的，该突变编码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，SBD及其SBD基因的启动子，并开发了用于SBD的受控表达的工具。 令人着迷的是，这种综合症患有白血病的几乎所有患者都会损失染色体7。在许多儿科和成年患者AML/MDS患者中也发现了这种异常。 虽然在7q染色体上有一个最小删除的区域，但该肿瘤抑制剂的身份尚不清楚。 我们将在模型系统中测试几个候选基因。 通过识别遗传共同模型并确定它们如何干扰造血剂，我们将能够最终设计预防性策略，并为已经开发AML/MD的人设计更有效的疗法。 此外，由于Shwachman-Diamond综合征还会导致胰腺功能不全，增长障碍和发育障碍，因此我们的模型将增加其他生物学家和临床医生的价值。