Unravelling the ontogeny of clonal hematopoiesis and functional consequences in the stem cell compartment

最近，有研究表明，克隆造血，即体细胞血液病相关基因突变的存在，发生在至少10%的65岁以上无任何血液病史的人的外周血中。这种常见现象的存在构成恶性前状态，与血液癌风险增加和总体死亡率增加有关。克隆造血以年龄相关的方式发生，表明干细胞衰老与不同的基因突变之间存在密切联系。所有给出的数据都支持干细胞和/或祖细胞参与克隆造血的起源。根据这一假设，我们和其他人能够证明，一些受影响的基因突变可以在各种血液恶性肿瘤患者的造血干细胞（hsc）中被识别，包括急性髓系白血病（AML）、慢性髓单核细胞白血病（CMML）、骨髓增生异常综合征（MDS）和慢性淋巴细胞白血病（CLL），这表明这些突变很可能是血液肿瘤的疾病起始事件。该项目的总体目标是全面表征克隆造血，并研究其对没有任何血液疾病史的个体的功能影响。此外，我们的目标是揭示在造血分化的早期和后期阶段驱动恶性转化的遗传畸变和致癌网络。为了实现这一目标，我们提出以下具体目标：目的1：研究造血分化树中的突变负担，并定义克隆造血的分子个体发生。目的2：研究成熟细胞组分中基因突变的功能后果。目的3：鉴定克隆造血个体干细胞区室的突变特异性分化特性，并模拟人类脐带血系统干细胞衰老过程中基因突变的功能后果。

Recently, it has been shown that clonal hematopoiesis, defined by the presence of a somatic hematologic cancer associated gene mutation, occurs in the peripheral blood of at least 10% of persons older than 65 years of age without any history of hematologic disorders. The presence of this common phenomenon constitutes a pre-malignant state which is associated with an increased risk of hematologic cancers and an increased overall mortality. Clonal hematopoiesis occurs in an age-related manner indicating a close connection between stem cell aging and the distinct gene mutations. All given data advocates for stem cell and/or progenitor cell involvement as origin of clonal hematopoiesis. In line with this hypothesis, we and others were able to show that some of the affected gene mutations can be identified in hematopoietic stem cells (HSCs) of patients suffering from various hematologic malignancies including acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL), indicating that these mutations are very likely disease initiating events in hematologic neoplasms. The overall goal of the proposed project is to comprehensively characterize clonal hematopoiesis and study its functional impact in individuals without any history of hematologic disorders. Additionally, we aim to unravel genetic aberrations and oncogenic networks that drive malignant transformation at both early and late steps of hematopoietic differentiation. To achieve this we propose the following specific aims: Aim 1: To study the mutation burden across the hematopoietic differentiation tree and define the molecular ontogeny of clonal hematopoiesis. Aim 2: To study the functional consequences of gene mutations in mature cell fractions. Aim 3: To identify mutation-specific differentiation properties in the stem cell compartment of individuals with clonal hematopoiesis and modelling functional consequences of gene mutations during stem cell aging in human cord blood systems.