The Role of Somatic Mutations in Aplastic Anemia

体细胞突变在再生障碍性贫血中的作用

• 批准号: 8942834
• 负责人: Jaroslaw P Maciejewski
• 金额: $ 39.63万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8942834
• 关键词: Address; Aplastic Anemia; Architecture; Cell Fraction; Cells; Clinical; Clonal Evolution; Complication; Cross-Sectional Studies; Cytogenetics; Defect; Detection; Development; Diagnosis; Diagnostic; Disease; Dysmyelopoietic Syndromes; Evaluation; Event; Evolution; Frequencies; Gene Frequency; Genes; Genetic; Genome; Germ Lines; Hematopoiesis; Hematopoietic; Immune; Immune response; Immune system; Immunosuppression; Karyotype determination procedure; Lead; Lesion; Malignant - descriptor; Molecular; Mutate; Mutation; Mutation Analysis; Myeloid Cells; Pathogenesis; Patients; Pattern; Probability; Reaction; Risk; Role; Sampling; Sequence Analysis; Somatic Mutation; Speed; Staging; Stem cells; Technology; Therapeutic immunosuppression; Uncertainty; Variant; accurate diagnosis; base; chromosome 7q loss; cohort; cross reactivity; deep sequencing; density; improved; leukemia; new technology; next generation sequencing; pressure; progenitor; prognostic; public health relevance; response; screening; theories; tumor

 DESCRIPTION (provided by applicant): The key aspect of the conceptual framework in the pathogenesis of aplastic anemia (AA) relates to the events that can trigger immune attacks directed against hematopoietic progenitor and stem cells. Immune tumor surveillance reactions to emerging clonal outgrowth with a cross-reactivity and collateral damage to the stem cell compartment have been proposed among various types of self-directed immune responses in AA. This possibility fits with the close pathophysiologic association of AA with clonal myelodysplastic syndromes (MDS). The latter is a common late-stage complication of AA and constitutes, in its hypocellular form, an alternative diagnosis in misdiagnosed AA because of the lack of sufficient cells for cytomorphologic or cytogenetic evaluation. An alternative theory explaining the pathophysiological relationship of AA to clonal diseases of hematopoiesis relates to the possibility that oligoclonality due to stem cell depletion may lead to a higher probability f recruitment of defective stem cells. New molecular technologies, including high-density SNP arrays and next generation sequencing (NGS), have created opportunities for study of the molecular pathogenesis of AA. These new technologies allow for unbiased screens for mutations involving major portions of the genome. They also allow for high sensitivity and analysis of clonal architecture. Our preliminary results suggest that clonal events may be detected in AA at presentation or occur very early in the course of the disease. While the presence of somatic mutations may not necessarily result in MDS in every instance, it is likely that if subsequent MDS develops it happens on the basis of these lesions. In this proposal we hypothesize that clonal events may be detected at initial presentation in a proportion of AA patients, and that certain clonal events are permissive and lead to late clonal evolution and progression through acquisition of secondary events, while others may be eradicated by the immune system. The objectives of this project are to assess the proportion of AA patients harboring somatic clonal lesions and determine the prognostic significance and diagnostic utility of such genetic defects in terms of response to immunosuppression and clonal evolution. In addition we hope to identify ancestral events in these patients that determine which secondary events lead to MDS. We will screen cohorts of patients with AA as well as post-AA clonal evolution, including MDS and PNH, for the presence of somatic clonal lesions during the course of their disease. By serial and cross-sectional analysis we will investigate hierarchical clonal architecture consisting of somatic mutations and chromosomal analysis. Finally, we will establish clinical correlations and the prognostic impact of these clonal somatic events. Clinical analyses will be performed to determine the impact of somatic mutations on risk of evolution vs. sub clonal persistence, response/refractoriness to immunosuppression, and the speed and dynamics of PNH persistence or evolution. We postulate that addressing these important questions in AA may lead to paradigm-shifting concepts in the understanding of this disease.

 描述（由申请人提供）：再生障碍性贫血（AA）发病机制的概念框架的关键方面涉及可引发针对造血祖细胞和干细胞的免疫攻击的事件，以及对新出现的克隆生长的免疫肿瘤监视反应。已提出 AA 中各种类型的自我定向免疫反应之间存在交叉反应性和对干细胞区室的附带损害，这​​种可能性符合 AA 与克隆的密切病理生理学关联。后者是 AA 的常见晚期并发症，由于缺乏足够的细胞进行细胞形态学或细胞遗传学评估，其细胞减少形式构成了误诊 AA 的另一种诊断。 AA 与造血克隆疾病的关系与干细胞耗竭导致的寡克隆性可能导致缺陷干细胞招募的可能性更高有关。包括高密度 SNP 阵列和下一代测序 (NGS) 在内的新技术为研究 AA 的分子发病机制创造了机会，这些新技术可以对涉及基因组主要部分的突变进行公正的筛查，并且还可以实现高灵敏度。我们的初步结果表明，克隆事件可能在 AA 中被发现或在病程的早期发生，虽然体细胞突变的存在不一定会导致 MDS，但很可能会发生。那如果随后的 MDS 发展是在这些病变的基础上发生的，在本提案中，我们追求在部分 AA 患者中最初出现时可以检测到克隆事件，并且某些克隆事件是允许的，并通过获得导致晚期克隆进化和进展。该项目的目标是评估携带体细胞克隆病变的 AA 患者的比例，并确定此类遗传缺陷在免疫抑制和免疫反应方面的预后意义和诊断效用。此外，我们希望确定这些患者的祖先事件，以确定哪些继发事件导致 MDS。我们将筛选 AA 患者队列以及 AA 后克隆进化（包括 MDS 和 PNH）是否存在体细胞。通过连续和横断面分析，我们将研究由体细胞突变和染色体分析组成的分层克隆结构，最后，我们将建立这些克隆体细胞的临床相关性和预后影响。将进行临床分析以确定体细胞突变对进化风险与亚克隆持久性、对免疫抑制的反应/难治性以及 PNH 持久性或进化的速度和动态的影响，我们假设解决了 AA 中的这些重要问题。可能会导致对这种疾病的理解发生范式转变。