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: 10389077
• 负责人: Jacob Stauber
• 金额: $ 5.18万
• 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/10389077
• 关键词: Affect; Age; Aging; Allogenic; Architecture; Biological Assay; Blood; Blood Cells; Blood specimen; Bone Marrow; Cardiovascular Diseases; Case Study; Cell Aging; Cell Differentiation process; Cells; Clonal Evolution; Clonal Expansion; Clonal Hematopoietic Stem Cell; Complication; DNA; Development; Donor Selection; Donor person; Elderly; Environment; Epigenetic Process; Evolution; Future; Genes; 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; Recording of previous events; Regimen; Relapse; Reporting; Residual state; Resources; Risk; Risk Assessment; Role; Sampling; Siblings; Somatic Mutation; Stimulus; Stress; Surface; System; Testing; Time; Transplant Recipients; Transplantation; cardiovascular disorder risk; chronic graft versus host disease; conditioning; cytopenia; deep sequencing; 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; 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.

项目概要 克隆造血 (CH)，定义为造血克隆的不成比例代表性 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，并且 与心血管疾病和全因死亡率风险增加有关。 我们有兴趣在同种异体造血细胞移植的背景下研究 CH （HCT）。由于老龄化受者和相关捐献者数量不断增加，捐献者样本中的 CH 正变得越来越严重。 越来越有可能。先前的研究表明，供体 CH 与供体细胞白血病有关，并增加了罹患供体细胞白血病的风险。 不明原因的血细胞减少症和慢性移植物抗宿主病，并显示出 CH 的优先扩增 移植后克隆。矛盾的是，供体 CH 也与复发风险降低有关。邮政- 在移植过程中，供体 CH 克隆由于其快速自我更新和炎症骨而承受着特殊的压力 骨髓微环境。然而，人们对克隆动力学和进化知之甚少。 移植后的骨髓及其与报告结果的关系。此外，尚不清楚CH如何 与分化细胞相比，造血干细胞 (HSC) 群体中代表的克隆。 在这个项目中，我们建议定义单细胞同种异体 HCT 后的克隆动力学和进化 等级。我们的目标是了解供体克隆和受体克隆之间的相互作用、它们如何发育和 分布在造血谱系中，以及供体 CH 克隆如何影响这些过程。为了实现这一目标， 我们将利用 HCT 接受者在术后头两年收集的纵向骨髓样本 移植。我们将应用一种新的高通量单细胞系统，该系统允许同时进行基因型和 每个细胞的表型信息。使用这些信息，我们将能够跟踪进化、扩展、 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。 外周血以识别 HSC 中优先发现的克隆并追踪它们在成熟细胞中的出现 血细胞。总体而言，该项目将有助于更好地了解捐助者 CH 的风险以及驱动因素 这些风险。我们获得的见解对于理解干细胞亚克隆动力学和 压力条件下的竞争和一般白血病进展。