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: 10570931
• 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/10570931
• 关键词: Acceleration; Acute Myelocytic Leukemia; Address; Adverse event; Affect; Age; Age Years; Aged, 80 and over; Aging; Allogeneic Bone Marrow Transplantation; 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; DNMT3a; 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; 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; Proliferating; Prospective Studies; Publishing; Risk Factors; Role; Sampling; Solid Neoplasm; Somatic Mutation; Study models; Testing; Time; Tissues; Toxic effect; adverse outcome; age group; age related; clinically relevant; cohort; follow-up; genetic evolution; graft vs host disease; human model; human very old age (85+); improved; in vivo; insight; leukemia; leukemogenesis; longitudinal, prospective study; patient stratification; personalized therapeutic; post-transplant; pre-clinical; premalignant; prognostic; progression risk; 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.

不确定潜能的克隆性造血（CHIP）定义为获得体细胞突变， 造血细胞是一种常见的与年龄相关的病症。CHIP的患病率在所有年龄段均超过12% 组和近50%的受试者年龄超过85岁。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性转化是一个明显的问题。即使 CHIP相对常见，进展为临床明显疾病的风险较低（每年<1%）， 进展的确切机制在很大程度上是未知的。因此，对患者进行适当的风险分层 挑战性除了其致白血病的潜力，CHIP也是慢性白血病的独立危险因素。 炎症、心血管疾病，并与一般人群的不良结局相关， 在实体瘤患者中。解决克隆造血临床影响的一种方法是鉴定 并前瞻性地随访了一大批CHIP患者。然而，这种方法需要大量的 受试者数量多，随访时间长。在进行长期前瞻性研究的同时，我们建议 研究CHIP的自然史、临床后果以及克隆扩张的机制 同种异体血液或骨髓移植（alloBMT）。我们之前已经发表过临床上沉默的 克隆（在供体内的自我平衡条件下）扩增并在增强的免疫应答期间被选择。 在受体中重建造血所需的增殖和自我更新;这意味着alloBMT 大大加快了CHIP的自然历史，这应该使我们能够捕捉到遗传进化，克隆， 动力学和临床后遗症的CHIP在加速的时间框架。我们将1）确定致癌的 供者来源的CHIP在alloBMT受者中的潜在和非恶性不良结局。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 低频率克隆的致癌潜力，并将真正的疾病驱动因素与背景遗传因素区分开来 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 3）阐明克隆生长优势的表观遗传畸变和细胞途径; 确定CHIP对近10，000名女性亚临床实体瘤发病率的影响 参与DETECT试验，并确定CHIP在肿瘤发生和进展中的作用。的 上述方法将使我们能够1）更好地确定致癌潜力和表观遗传畸变， 癌前克隆以及供体CHIP在alloBMT受体中的非恶性后果; 2）我们的 一项前瞻性研究不仅将深入了解CHIP患者的风险分层， 为研究克隆进化和体内白血病发生提供了一个非常重要的人体模型。3)我们将更好 定义CHIP对亚临床肿瘤的影响，我们的研究结果可能导致实施 最适当的治疗，以避免治疗相关的恶性肿瘤和心血管毒性。