The Biological Consequences of Age-related Clonal Hematopoiesis

年龄相关克隆造血的生物学后果

• 批准号: 10348166
• 负责人: Lukasz Pawel Gondek
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-10 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10348166
• 关键词: Acute Myelocytic Leukemia; Address; Adverse event; Affect; Age; Age-Years; Aged, 80 and over; Aging; Allogenic; Biological; Biology; Blood; Blood Cells; Bone Marrow; Bone Marrow Transplantation; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Clinical; Clinical Data; Clonal Evolution; Clonal Expansion; Cohort Studies; Complication; Data; Development; Disease; Donor Selection; Donor person; Dysmyelopoietic Syndromes; Elderly; Enrollment; Epigenetic Process; Event; Female; Frequencies; Future; General Population; Genes; Genetic; Growth; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Incidence; Individual; Inferior; Inflammation; Inflammatory; Length; Leukemic Cell; Longitudinal prospective study; Malignant - descriptor; Malignant Neoplasms; Mutation; Natural History; Nature; Non-Hematologic Malignancy; Non-Malignant; Oncogenic; Outcome; Pathway interactions; Patients; Persons; Phenotype; Populations at Risk; Prevalence; Prevention strategy; Process; Prospective Studies; Publishing; Risk; Risk Factors; Role; Sampling; Solid Neoplasm; Somatic Mutation; Study models; Testing; Time; Tissues; Toxic effect; Transplant Recipients; adverse outcome; age group; age related; clinically relevant; cohort; follow-up; genetic evolution; graft vs host disease; human model; improved; in vivo; insight; leukemia; leukemogenesis; patient stratification; personalized therapeutic; post-transplant; pre-clinical; premalignant; prognostic; prospective; risk stratification; screening; self-renewal; tumor

Clonal hematopoiesis of indeterminate potential (CHIP) defined as acquisition of somatic mutations in hematopoietic cells is a common age-related condition. The prevalence of CHIP exceeds 12% over all age groups and nearly 50% for subjects older than 85 years. Since somatic mutations frequently affect putative cancer drivers the malignant transformation to myelodysplasia or leukemia is an obvious concern. Even though CHIP is relatively common, the risk of progression to clinically apparent disease is low (<1% per year) and the exact mechanism of progression is largely unknown. Thus, the appropriate risk-stratification of patients remains challenging. In addition to its leukemogenic potential, CHIP is also an independent risk factor of chronic inflammation, cardiovascular disease and has been associated with inferior outcome in general population and in patients with solid tumors. One approach to address the clinical impact of clonal hematopoiesis is to identify and prospectively follow a large cohort of individuals with CHIP. However, this approach would require large number of subjects and long follow-up period. While the long-term prospective studies are underway we propose to study the natural history and clinical consequences and the mechanism of clonal expansion of CHIP in allogeneic blood or marrow transplantation (alloBMT) setting. We have previously published that clinically silent clones (under homeostatic conditions within the donor) expand and are selected for during the enhanced proliferation and self-renewal required to re-establish hematopoiesis in the recipient; this implies that alloBMT greatly hastens the natural history of CHIP, which should allow us to capture the genetic evolution, clonal dynamics, and clinical sequelae of CHIP in an accelerated time-frame. We will 1) determine the oncogenic potential and non-malignant adverse outcome of donor-derived CHIP in alloBMT recipients. Studying the cohort of 1,857 bone marrow donors above the age of 40 as well as serial samples and clinical data we will better define the oncogenic potential of low-frequency clones and distinguish true disease drivers from background genetic events related to aging and examine the role of donor CHIP on non-malignant adverse events in alloBMT recipients; 3) elucidate the epigenetic aberration and cellular pathway involved in clonal growth advantage; 3) determine the impact of CHIP on the incidence of subclinical solid tumors studying nearly 10,000 females enrolled on DETECT trial and define the role of CHIP in tumor development and progression. The aforementioned approach will allow us 1) to better define the oncogenic potential and epigenetic aberrations in pre-malignant clones as well as non-malignant consequences of donor CHIP in alloBMT recipients; 2) our prospective study will not only provide an insight into the risk stratification of patients with CHIP but will also provide a very important human model for studying clonal evolution and leukemogenesis in vivo. 3) we will better define the impact of CHIP on subclinical tumors and the results from our study may result in implementation of most appropriate therapies in order to avoid therapy-related malignancies and cardiovascular toxicities.

不确定潜力克隆造血（CHIP）定义为体细胞突变的获得 造血细胞损伤是一种常见的与年龄相关的疾病。所有年龄段的 CHIP 患病率超过 12% 组中，85 岁以上受试者的比例接近 50%。由于体细胞突变经常影响假定的 癌症导致骨髓增生异常或白血病的恶变是一个明显的问题。虽然 CHIP 相对常见，进展为临床明显疾病的风险较低（每年 <1%），并且 确切的进展机制在很大程度上尚不清楚。因此，患者的适当风险分层仍然存在 具有挑战性的。除了其潜在的致白血病潜力外，CHIP 也是慢性病的一个独立危险因素。 炎症、心血管疾病，并与普通人群的不良预后相关 实体瘤患者。解决克隆造血临床影响的一种方法是确定 并前瞻性地跟踪一大群 CHIP 患者。然而，这种方法需要大量 受试者数量多，随访时间长。虽然长期前瞻性研究正在进行中，但我们建议 研究 CHIP 的自然史和临床后果以及克隆扩增的机制 同种异体血液或骨髓移植（alloBMT）环境。我们之前曾发表过临床沉默的 克隆（在供体内的稳态条件下）扩增并在增强过程中进行选择 受体内重建造血功能所需的增殖和自我更新；这意味着 alloBMT 极大地加速了 CHIP 的自然历史，这将使我们能够捕捉基因进化、克隆 加速时间范围内 CHIP 的动力学和临床后遗症。我们将 1) 确定致癌物质 供体来源的 CHIP 对 alloBMT 受者的潜在和非恶性不良后果。研究队列 1,857 名 40 岁以上的骨髓捐献者以及系列样本和临床数据我们将更好地定义 低频克隆的致癌潜力，并将真正的疾病驱动因素与背景遗传区分开来 与衰老相关的事件并检查供体 CHIP 对 alloBMT 中非恶性不良事件的作用 收件人； 3）阐明表观遗传畸变和涉及克隆生长优势的细胞途径； 3） 研究近 10,000 名女性以确定 CHIP 对亚临床实体瘤发病率的影响 参加 DETECT 试验并确定 CHIP 在肿瘤发生和进展中的作用。这 上述方法将使我们能够1）更好地定义致癌潜力和表观遗传畸变 alloBMT 受者中供体 CHIP 的癌前克隆以及非恶性后果； 2）我们的 前瞻性研究不仅可以深入了解 CHIP 患者的风险分层，还可以 为研究体内克隆进化和白血病发生提供了非常重要的人类模型。 3）我们会更好 定义 CHIP 对亚临床肿瘤的影响，我们的研究结果可能会导致实施 最合适的治疗方法，以避免治疗相关的恶性肿瘤和心血管毒性。