UNDERSTANDING STEM-CELL EVOLUTION DYNAMICS OF DONOR CLONAL HEMATOPOIESIS IN ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION AT A SINGLE-CELL LEVEL

在单细胞水平了解同种异体造血细胞移植中供体克隆造血的干细胞进化动力学

• 批准号: 10633068
• 负责人: Jacob Stauber
• 金额: $ 5.27万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10633068
• 关键词: Acceleration; Affect; Age; Aging; Allogenic; Architecture; Biological Assay; Blood; Blood Cells; Blood specimen; Bone Marrow; Cardiovascular Diseases; Case Study; Cell Aging; Cell Differentiation process; Cell Separation; Cells; Clonal Evolution; Clonal Expansion; Clonal Hematopoietic Stem Cell; Complication; DNA; Development; Donor Selection; Elderly; Environment; Epigenetic Process; Evolution; Future; Genes; Genetic Transcription; Genotype; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Individual; Inflammatory; Label; Length; Leukemic Cell; Malignant Neoplasms; Mutate; Mutation; Myeloproliferative disease; Outcome; Pattern; Persons; Phenotype; Population; Prevalence; Process; Proliferating; Recording of previous events; Regimen; Relapse; Reporting; Residual state; Resources; Risk; Risk Assessment; Role; Sampling; Siblings; Somatic Mutation; Sorting; Stimulus; Stress; Surface; System; Testing; Time; Transplant Recipients; Transplantation; cardiovascular disorder risk; chronic graft versus host disease; conditioning; cytopenia; deep sequencing; dynamical evolution; experience; follow-up; genetic analysis; graft vs leukemia effect; hematopoietic cell transplantation; in vivo; inflammatory milieu; insight; interest; leukemia; leukemogenesis; mortality; mutant; older patient; peripheral blood; post-transplant; premature; pressure; progression risk; protein expression; relapse risk; response; screening; segregation; self-renewal; stem; stem cell population; stem cells; telomere

PROJECT SUMMARY Clonal hematopoiesis (CH), as defined by the disproportionate representation of hematopoietic clones with somatic mutations, is highly prevalent in the elderly. CH confers a risk of progression to malignancy and has been associated with increased risk of cardiovascular disease and all-cause mortality. We are interested in studying CH specifically in the context of allogeneic hematopoietic cell transplantation (HCT). Due to the increasing number of aging recipients and related donors, CH in donor samples is becoming increasingly likely. Previous studies have implicated donor CH in donor cell leukemias and an increased risk of unexplained cytopenias and chronic graft-versus-host disease, and have shown preferential expansion of CH clones post-transplant. Paradoxically, donor CH has also been associated with reduced risk of relapse. Post- transplant, donor CH clones are under particular stress due to their rapid self-renewal and the inflammatory bone marrow microenvironment. However, little is known about the clonal dynamics and evolution that occurs in the bone marrow post-transplant and how they relate to the reported outcomes. Additionally, it is not clear how CH clones represented in the hematopoietic stem cell (HSC) populations compared to differentiated cells. In this project we propose to define the clonal dynamics and evolution post-allogeneic HCT at the single cell level. Our goal is to understand the interactions between the donor and recipient clones, how they develop and distribute across hematopoietic lineages, and how donor CH clones affect these processes. To achieve this goal, we will utilize longitudinal bone marrow samples from HCT recipients collected in the first two years post- transplant. We will apply a new high-throughput single cell system that allows for simultaneous genotypic and phenotypic information for each cell. Using this information, we will be able to track the evolution, expansion, and lineage distribution of each clone, and examine the role of pre-existing donor CH clones on this process. Additionally, we will compare the clonal architectures of the bone marrow HSC population with that of total peripheral blood to identify clones that are preferentially found in HSCs and track their emergence in mature blood cells. Overall, this project will provide a greater understanding of the risks in donor CH and what drives these risks. The insights we gain will also be valuable in understanding stem cell subclonal dynamics and competition under stress conditions and leukemic progression in general.

项目摘要 克隆性造血（CH），定义为造血克隆的不成比例表达， 体细胞突变在老年人中非常普遍。CH具有进展为恶性肿瘤的风险， 与心血管疾病和全因死亡率的风险增加有关。 我们有兴趣在异基因造血细胞移植的背景下专门研究CH （HCT）。由于老年受者和亲属供者数量的增加，供者样本中的CH正成为 越来越有可能。以前的研究表明，供体CH与供体细胞白血病有关， 不明原因的血细胞减少症和慢性移植物抗宿主病，并显示CH的优先扩张 移植后的克隆巧合的是，供体CH也与复发风险降低相关。后 在移植中，供体CH克隆由于其快速自我更新和炎性骨而处于特别的压力下 骨髓微环境然而，很少有人知道克隆动态和进化发生在 移植后骨髓以及它们与报告结果的关系。此外，尚不清楚CH 与分化的细胞相比，造血干细胞（HSC）群体中代表的克隆。 在这个项目中，我们建议在单个细胞中定义同种异体HCT后的克隆动力学和进化 水平我们的目标是了解供体和受体克隆之间的相互作用，它们是如何发展的， 分布在造血谱系，以及供体CH克隆如何影响这些过程。为了实现这一目标， 我们将使用在移植后的头两年收集的HCT接受者的纵向骨髓样本， 移植我们将应用一种新的高通量单细胞系统，允许同时进行基因型和 每个细胞的表型信息。利用这些信息，我们将能够跟踪进化，扩张， 和每个克隆的谱系分布，并检查预先存在的供体CH克隆在此过程中的作用。 此外，我们将比较骨髓HSC群体的克隆结构与总HSC群体的克隆结构。 外周血，以鉴定优先在HSC中发现的克隆，并追踪它们在成熟造血干细胞中的出现。 血细胞总的来说，本项目将使人们更好地了解供体CH的风险， 这些风险。我们获得的见解也将是有价值的理解干细胞亚克隆动力学， 压力条件下的竞争和一般白血病进展。