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

基本信息

批准号：
10228701
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
项目类别：
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/10228701
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 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 risk stratification single-cell RNA sequencing surveillance strategy targeted sequencing targeted treatment therapeutic target transcriptome transcriptomics treatment strategy whole genome young adult

项目摘要

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.

项目概要/摘要骨髓衰竭 (BMF) 的特点是血细胞生成不足，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 是最常见于老年人，是由获得体细胞突变引起的，导致细胞过多骨髓和造血功能无效。相比之下，MDS 在儿童和年轻人中更为常见与种系遗传易感性和细胞少的骨髓有关。然而，综合症特征或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。这鉴定 BMF/MDS 种系遗传易感性至关重要，因为它可以为医疗管理和治疗提供信息提供了监测和早期干预的机会。临床护理的根本障碍 BMF/MDS 患者的致病基因目录不完整，并且无法准确预测进展为骨髓恶性肿瘤的风险。因此，本研究的目的是：目的 1) 改善诊断通过鉴定患者的新基因和变异来研究 BMF/MDS 的种系遗传易感性靶向测序和 WES 无法诊断，目标 2) 鉴定体细胞基因组， BMF/MDS 疾病进展的转录组和表观基因组驱动因素，目的是提供信息患者的纵向管理。我们首先将重点关注 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综合分析 SDS 的特点，目的是加深对体细胞克隆进展的理解定义的临床队列。该方法随后将扩展到包括患有其他 BMF/MDS 疾病的患者在学习的最后几年。该项目汇集了一个由具有专业知识的研究人员组成的综合团队儿科和成人 BMF/MDS、种系遗传学、体细胞基因组学、表观基因组学和转录组学。这项目利用了不断增长的、预先存在的、带注释的 BMF/MDS 样本存储库纵向来自儿科和成人患者及其家人。与使命一致 RC2，这些研究生成的临床注释数据集将可供医学和医学界使用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中。