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: 10454344
• 负责人: MARK D FLEMING
• 金额: $ 127.1万
• 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/10454344
• 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; Bone marrow failure; 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; Pathway interactions; Patients; Phenotype; Physicians; Prevention strategy; Production; RNA Sequences; Recording of previous events; Registries; Research Personnel; Resources; Risk; Role; Sampling; Science; Shwachman-Diamond syndrome; Somatic Mutation; Specimen; 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; risk stratification; 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）的特征是血细胞的产生不足，通常与 进展到骨髓增生综合征（MDS）或急性髓样白血病的风险增加。 MDS是最大的 在老年人中很常见，这是由于获取导致高细胞的体细胞突变引起的 骨髓和无效的造血。相比之下，儿童和年轻人的MDS更常见 与种系遗传倾向和低细胞骨髓有关。但是，综合征特征或 通常不存在清晰的家族史，因此所有年轻患者必须考虑遗传的BMF/MD。这 生殖线对BMF/MD的种系遗传易感性至关重要，因为它可以为医疗管理和 为监视和早期干预提供了机会。临床护理的基本障碍 BMF/MDS患者包括因果基因的不完整目录，无法准确预测 进展到髓样恶性肿瘤的风险。因此，这项研究的目的是：目标1）改进诊断 通过鉴定患者的新基因和变异的生殖线遗传倾向 针对的测序和WE为非诊断，目标2）确定体细胞基因组， BMF/MD的疾病进展的转录组和表观基因组驱动力，目的是告知 患者的纵向管理。我们最初将专注于Shwachman-Diamond综合征（SDS） 鉴定新的SDS基因并进行基因组，分子和临床的纵向，综合分析 SD的特征，目的是在这种良好的范围内了解对躯体克隆进展的理解 定义的临床队列。然后将扩展此方法，包括其他BMF/MDS疾病的患者 在研究的后期。该项目汇集了一个具有专业知识的调查员团队 小儿和成人BMF/MD，种系遗传学，体细胞基因组学，表观基因组学和转录组学。这 收集的BMF/MDS标本的项目杠杆不断增长，已存在的注释存储库 来自儿科和成年患者及其家人的纵向。与任务一致 RC2，这些研究生成的临床注释的数据集将很容易适用于医疗和 通过公共平台来促进BMF/MD的科学，发现和临床护理的科学社区 在儿童和年轻人中。