Defining the scope and clinical impact of donor CHIP after allogeneic HCT

定义同种异体 HCT 后供体 CHIP 的范围和临床影响

• 批准号: 10465095
• 负责人: Robert Coleman Lindsley
• 金额: $ 56.52万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-14 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10465095
• 关键词: Age; Age-Years; Allogenic; Archives; Bar Codes; Biological; Biology; Cardiovascular system; Cells; Characteristics; Clinical; Clonal Evolution; Clone Cells; Cytokine Signaling; Data; Development; Donor Selection; Donor person; Effector Cell; Engraftment; Epigenetic Process; Frequencies; Functional disorder; Genetic; Gold; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homologous Transplantation; Human; Immune; Immune System Diseases; Impairment; Infection; Inferior; Inflammatory; Laboratories; Lead; Leukemic Cell; Link; Measures; Mediating; Medical Genetics; Modality; Modeling; Morbidity - disease rate; Mutation; Mutation Detection; Myeloproliferative disease; Non-Malignant; Outcome; Pathology; Patients; Production; Property; Recovery; Recurrent disease; Relapse; Reporting; Risk; Safety; Sampling; Stem Cell Development; Technology; Testing; Time; Transplant Recipients; Transplantation; Universities; Validation; Work; age related; base; chronic graft versus host disease; clinically significant; cohort; curative treatments; cytokine; cytopenia; donor stem cell; fitness; genetic approach; genetic evolution; graft dysfunction; graft function; graft vs host disease; high risk; immune function; immune reconstitution; immunoregulation; improved; improved outcome; innovation; insight; mortality; next generation sequencing; novel strategies; post-transplant; sequencing platform; stem cell engraftment; stem cells; success; tool; transcriptome; transcriptomics

PROJECT SUMMARY Allogeneic hematopoietic stem cell transplantation (HSCT) involves the transfer of healthy donor hematopoietic cells, including hematopoietic stem cells and mature immune effector cells, to recipients with high-risk hematologic malignancies. The success of HSCT is fundamentally dependent on engraftment of normal donor- derived hematopoiesis. Inadequate graft function can cause a range of complications that impact recipient outcomes, including disease relapse, graft versus host disease, and infection. In preliminary studies, we identified healthy stem cell donors with clonally restricted hematopoiesis, marked by mutations in canonical genetic drivers of myeloid malignancies, where the aberrant clone engrafted in a transplant recipient, underwent selective expansion, and was associated with abnormal hematopoietic function. While rare patients developed donor cell leukemia after long latency, our data suggest that non-malignant outcomes of donor-engrafted clonal hematopoiesis, such as hematopoietic dysfunction or graft versus host disease may be more common and may manifest earlier after transplantation, thereby contributing significantly to transplant-related morbidity. We hypothesize that the presence of clonal hematopoiesis of indeterminate potential (CHIP) is an age-independent predictor of donor hematopoietic fitness that negatively impacts recipient outcome by causing impaired graft function. This proposal combines complementary genetic, functional, and transcriptomic approaches in a large cohort of stem cell donor-recipient pairs to define the impact of donor CHIP on allo HSCT outcomes. In Specific Aim 1, we will determine the frequency and clinical significance of CHIP in a 1911 allogeneic stem cell donors 40 years of age and older (discovery cohort,n=1189; external validation cohort, n=722). To complete this aim, we have developed and validated a highly sensitive sequencing platform for identification of CHIP in donor samples, with >50-fold greater sensitivity than standard next generation sequencing modalities. This work will be closely linked to Specific Aim 2, where we will focus on the subset of donors with clonal mutations to define the efficiency and lineage potential of clonal stem cell engraftment, and the genetic evolution of clones over time. Finally, in Specific Aim 3 we will dissect the functional impact of donor CHIP on immune function in transplant recipients, testing the hypothesis that stem cell clones can perturb inflammatory cytokine production and proper recovery of immune activity via their clonal contribution to mature immune cell subsets. Together, the proposed studies may define a new paradigm of donor-attributable risk in allogeneic HSCT and provide insights into biological mechanisms of clonal dominance and the influence of microenvironmental context on clonal evolution.

项目摘要 异基因造血干细胞移植（HSCT）涉及将健康供体的造血干细胞转移到骨髓中。 细胞，包括造血干细胞和成熟的免疫效应细胞，以高风险 血液恶性肿瘤HSCT的成功从根本上取决于正常供体的植入- 衍生造血移植物功能不足可导致一系列影响受体的并发症 结果，包括疾病复发，移植物抗宿主病和感染。在初步研究中，我们 确定了具有克隆限制性造血的健康干细胞供体，其特征是典型的 骨髓恶性肿瘤的遗传驱动因素，其中异常克隆植入移植受体， 选择性扩增，并与造血功能异常有关。虽然罕见的患者 对于长潜伏期后的供体细胞白血病，我们的数据表明， 造血作用，如造血功能障碍或移植物抗宿主病可能更常见，并可 在移植后较早出现，从而显著促进移植相关的发病率。我们 假设不确定潜能的克隆性造血（CHIP）的存在是年龄无关的， 通过导致移植物受损而对受体结果产生负面影响的供体造血适应性的预测因子 功能该建议结合了互补的遗传，功能和转录组学方法， 干细胞供体-受体对的队列，以确定供体CHIP对allo HSCT结果的影响。在特定 目的1：在1911例异基因造血干细胞供者中，检测CHIP的发生率及其临床意义 40岁及以上（发现队列，n=1189;外部验证队列，n=722）。为了实现这一目标， 我们已经开发并验证了一个高灵敏度的测序平台，用于鉴定供体中的CHIP 样品，灵敏度比标准的下一代测序模式高>50倍。这项工作将 与特定目标2密切相关，在该目标中，我们将重点关注具有克隆突变的供体子集，以定义 克隆干细胞移植的效率和谱系潜力，以及克隆随时间的遗传进化。 最后，在具体目标3中，我们将剖析供体CHIP对移植免疫功能的功能影响 接受者，测试干细胞克隆可以扰乱炎症细胞因子的产生和适当的细胞因子的假设。 通过它们对成熟免疫细胞亚群的克隆贡献恢复免疫活性。在一起，拟议的 研究可能定义一种新的同种异体造血干细胞移植供体归因风险的范例， 克隆优势的生物学机制和微环境对克隆进化的影响。