Systems Biology of Bone Marrow Failure and MDS for Precision Medicine

骨髓衰竭和 MDS 的系统生物学用于精准医学

• 批准号: 10018490
• 负责人: MARK D FLEMING
• 金额: $ 127.88万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018490
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Affect; Atlases; Biological Markers; Biology; Blood; Blood Cell Count; Blood Cells; Blood specimen; Bone Marrow Examination; Bone Marrow Transplantation; CD34 gene; Candidate Disease Gene; Catalogs; Cells; Child; Childhood; Clinical; Clinical Research; Clonal Evolution; Communities; Complex; DNA Sequence Alteration; Data Set; Dependence; Diagnosis; Disease; Disease Progression; Dysmyelopoietic Syndromes; Early Intervention; Elderly; Epigenetic Process; Evolution; Family; Family member; Fibroblasts; Future; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Goals; Grant; Hematopoiesis; Individual; Ineffective Hematopoiesis; Inherited; Investigation; Life; Marrow; Medical; Mission; Molecular; Molecular Profiling; Mutation; Myeloproliferative disease; Outcome; Pain; Pancytopenia; Pathway interactions; Patients; Phenotype; Physicians; Prevention strategy; Production; RNA Sequences; Recording of previous events; Registries; Research Personnel; Resources; Risk; Risk stratification; Role; Sampling; Science; Shwachman-Diamond syndrome; Somatic Mutation; Specimen; Structure; Syndrome; System; Systems Analysis; Systems Biology; Technology; Time; Untranslated RNA; Variant; bone marrow failure syndrome; clinical care; clinical phenotype; cohort; epigenomics; exome sequencing; genetic disorder diagnosis; genetic variant; genome sequencing; genomic signature; human disease; improved; leukemia; longitudinal analysis; member; new therapeutic target; novel; phenome; precision medicine; prevent; repository; single-cell RNA sequencing; surveillance strategy; targeted sequencing; targeted treatment; therapeutic target; transcriptome; transcriptomics; treatment strategy; whole genome; young adult

Project Summary/Abstract Bone marrow failure (BMF) is characterized by inadequate blood cell production and is often associated with an increased risk of progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia. MDS is most common in older adults, where it is caused by acquisition of somatic mutations that cause hypercellular marrows and ineffective hematopoiesis. By contrast, MDS in children and young adults is more commonly associated with a germline genetic predisposition and hypocellular marrows. However, syndromic features or a clear family history are often absent, so inherited BMF/MDS must be considered in all young patients. The identification of germline genetic predisposition to BMF/MDS is critical as it informs medical management and provides an opportunity for surveillance and early intervention. Fundamental barriers to clinical care of BMF/MDS patients include an incomplete catalogue of causative genes and an inability to accurately predict risk for progression to myeloid malignancy. Therefore, the aims of this study are: Aim 1) Improve the diagnosis of germline genetic predisposition to BMF/MDS through identification of novel genes and variants in patients for whom targeted sequencing and WES were non-diagnostic, and Aim 2) Identify the somatic genomic, transcriptomic, and epigenomic drivers of disease progression in BMF/MDS with the goal of informing longitudinal management of patients. We will initially focus on Shwachman-Diamond syndrome (SDS) to identify new SDS genes and conduct a longitudinal, integrated analysis of the genomic, molecular, and clinical features of SDS, with the goal of developing an understanding of somatic clonal progression within this well- defined clinical cohort. This approach will then be expanded to include patients with other BMF/MDS disorders in the latter years of the study. This project brings together an integrated team of investigators with expertise in pediatric and adult BMF/MDS, germline genetics, somatic genomics, epigenomics, and transcriptomics. This project leverages ever-growing, pre-existing, annotated repositories of BMF/MDS specimens collected longitudinally from pediatric and adult patients and their family members. Consistent with the mission of the RC2, the clinically annotated datasets generated by these studies will be readily available to the medical and scientific communities through public platforms to promote science, discovery, and clinical care for BMF/MDS in children and young adults.

项目摘要/摘要 骨髓衰竭(BMF)的特征是血细胞生成不足，通常与 进展为骨髓增生异常综合征(MDS)或急性髓系白血病的风险增加。MDS是最多的 这在老年人中很常见，是由于获得了导致细胞增多的体细胞突变而引起的 骨髓和无效的造血。相比之下，儿童和年轻人中的MDS更常见 与生殖系遗传易感性和少细胞骨髓有关。然而，综合症特征或一种 通常没有明确的家族史，因此所有年轻患者都必须考虑遗传性BMF/MDS。这个 鉴定BMF/MDS的种系遗传易感性至关重要，因为它为医疗管理和 为监测和早期干预提供了机会。临床护理的基本障碍 BMF/MDS患者的致病基因目录不完整，无法准确预测 有发展为髓系恶性肿瘤的风险。因此，本研究的目的是：1)提高诊断率 通过鉴定患者的新基因和变异研究BMF/MDS的种系遗传易感性 对其而言靶向测序和WES是非诊断性的，并且目的2)鉴定体细胞基因组， BMF/MDS疾病进展的转录和表观基因组驱动因素，目的是告知 对病人的纵向管理。我们将首先关注Shwachman-Diamond综合征(SDS) 识别新的SDS基因并对基因组、分子和临床进行纵向、集成的分析 SDS的特征，目的是了解这口井内的体细胞克隆进程- 明确的临床队列。然后，这种方法将扩大到包括其他BMF/MDS疾病的患者 在研究的最后几年。该项目汇集了一支具有以下专业知识的综合调查团队 儿童和成人BMF/MDS、生殖系遗传学、体细胞基因组学、表观基因组学和转录组学。这 项目利用不断增长的、预先存在的、带注释的BMF/MDS样本收集资源库 纵向来自儿科和成人患者及其家属。与本组织的使命一致 RC2，由这些研究生成的临床注释数据集将随时可供医疗和 科学界通过公共平台促进BMF/MDS的科学、发现和临床护理 在儿童和年轻人身上。