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.

克隆性造血的不确定电位(CHIP)定义为获得体细胞突变 造血细胞是一种常见的年龄相关疾病。所有年龄段的CHIP患病率均超过12% 对于85岁以上的人群，这一比例接近50%。由于体细胞突变经常影响假定的 癌症驱动向骨髓发育不良或白血病的恶变是一个明显的问题。即使 芯片相对常见，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是未知的。因此，患者的适当风险分层仍然存在。 很有挑战性。CHIP除了具有潜在的白血病作用外，也是慢性粒细胞白血病的独立危险因素 炎症、心血管疾病，在一般人群中与不良结局有关 在实体瘤患者身上。解决克隆性造血临床影响的一种方法是确定 并前瞻性地跟踪一大批携带芯片的个人。然而，这种方法将需要大量的 受试者数量多，随访期长。虽然长期前瞻性研究仍在进行中，但我们建议 目的：研究CHIP克隆性扩张的自然病史、临床后果及机制。 异基因血液或骨髓移植(AllBMT)设置。我们之前已经发表了临床上的沉默 克隆(在供体内处于动态平衡状态下)在增强的过程中扩展和选择 需要增殖和自我更新来重建受者的造血；这意味着异体骨髓移植 极大地加速了芯片的自然历史，这应该可以让我们捕捉到遗传进化的克隆 动力学，以及加速时间范围内芯片的临床后遗症。我们将1)确定致癌因素 异基因骨髓移植受者中供体衍生芯片的潜在和非恶性不良后果。研究队列 在1,857名40岁以上的骨髓捐赠者以及系列样本和临床数据中，我们将更好地定义 低频率克隆的致癌潜力和区分真正的疾病驱动因素和背景基因 与衰老相关的事件和检测供体芯片在allBMT中非恶性不良事件中的作用 3)阐明克隆生长优势所涉及的表观遗传变异和细胞途径；3) 近10,000名女性研究确定芯片对亚临床实体肿瘤发病率的影响 登记参加检测试验并确定芯片在肿瘤发生和进展中的作用。这个 上述方法将允许我们1)更好地定义致癌潜力和表观遗传学异常 异基因骨髓移植受者中供体芯片的癌前克隆和非恶性后果；2)我们的 前瞻性研究不仅将深入了解CHIP患者的风险分层，还将 为研究体内克隆进化和白血病发生提供了非常重要的人体模型。3)我们会做得更好 定义芯片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，以避免与治疗相关的恶性肿瘤和心血管毒性。