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

揭示干细胞室中克隆造血的个体发育和功能后果

• 批准号: 284077802
• 负责人: Professor Dr. Frederik Damm
• 金额: --
• 依托单位: Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie (CVK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/284077802?language=en
• 关键词: Unravelling; ontogeny; clonal; hematopoiesis; functional

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.

最近，它已被证明，克隆造血，定义为体细胞血液癌相关基因突变的存在，发生在至少10%的人的外周血年龄超过65岁，没有任何历史的血液疾病。这种常见现象的存在构成了恶性前状态，其与血液系统癌症的风险增加和总体死亡率增加相关。克隆性造血以与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。所有给出的数据主张干细胞和/或祖细胞参与作为克隆造血的起源。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患有各种血液恶性肿瘤的患者的造血干细胞（HSC）中鉴定，这些血液恶性肿瘤包括急性髓性白血病（AML），慢性粒单核细胞白血病（CMML），骨髓增生异常综合征（MDS）和慢性淋巴细胞白血病（CLL），表明这些突变很可能是血液肿瘤中的疾病起始事件。该项目的总体目标是全面表征克隆造血，并研究其对无任何血液病史的个体的功能影响。此外，我们的目标是解开遗传畸变和致癌网络驱动恶性转化的早期和晚期造血分化的步骤。为了实现这一目标，我们提出了以下具体目标：目标1：研究整个造血分化树的突变负荷，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。目标3：识别具有克隆性造血的个体干细胞区室中突变特异性分化特性，并模拟人类脐带血系统干细胞老化期间基因突变的功能后果。