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.

不确定电势的克隆造血（芯片）定义为在 造血细胞是常见的年龄相关病。芯片的患病率在所有年龄段超过12％ 小组和近50％的受试者超过85岁。由于躯体突变经常影响推定 癌症驱动因素对脊髓增生或白血病的恶性转化是一个明显的关注点。虽然 芯片相对普遍，临床明显疾病的风险很低（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。除了其白血病潜力外，芯片也是慢性的独立危险因素 炎症，心血管疾病，与普通人群中的下降有关 在实体瘤患者中。解决克隆造血的临床影响的一种方法是确定 并前瞻性地跟随大量有芯片的人群。但是，这种方法需要大的 受试者的数量和较长的随访期。尽管正在进行长期前瞻性研究，但我们建议 研究自然历史和临床后果以及芯片克隆膨胀的机制 同种异体血液或骨髓移植（AlloBMT）设置。我们以前已经发表了临床上的沉默 克隆（在供体内的稳态条件下）扩展并在增强期间选择 在接受者中重新建立造血需要增殖和自我更新；这意味着Allobmt 极大地加速了芯片的自然历史，这应该使我们能够捕获遗传进化，克隆 加速时间框架中芯片的动力学和临床后遗症。我们将1）确定致癌 供体芯片的潜在和非机敏的不利结果在AlloBMT受体中。研究队列 超过40岁以上的1,857个骨髓供体以及串行样品和临床数据，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 与衰老有关的事件并检查捐助者芯片在AlloBMT中非机敏不良事件中的作用 接收者； 3）阐明涉及克隆生长优势的表观遗传像差和细胞途径； 3） 确定芯片对研究近10,000名女性的亚临床实体瘤发生率的影响 参加检测试验并定义了芯片在肿瘤发育和进展中的作用。这 上述方法将使我们1）更好地定义了在 在同种受体中，供体芯片的恶性克隆以及非机场后果； 2）我们的 前瞻性研究不仅会洞悉芯片患者的风险分层，而且还将 提供了一个非常重要的人类模型，用于研究克隆进化和体内白血病。 3）我们会更好 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 最合适的疗法以避免与治疗相关的恶性肿瘤和心血管毒性。