Integrated single cell multi-omic characterization and clonal tracing in clonal hematopoiesis

克隆造血中的综合单细胞多组学表征和克隆追踪

• 批准号: 497580500
• 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
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/497580500?language=en
• 关键词: Integrated; single; cell; multi; omic

Clonal hematopoiesis of indeterminate potential (CHIP) specifies an ageing-related state characterized by the acquisition of somatic mutations in hematopoietic stem cells (HSCs) and is associated with an increased risk of cardiovascular diseases (CVD), hematologic malignancies (HM) and all-cause mortality. CHIP-associated mutations affect malignancy-associated genes, that broadly fall into three major categories of genes including epigenetic regulators (e.g. DNMT3A, TET2, ASXL1), spliceosome (e.g. SF3B1) and DNA damage genes (e.g. PPM1D, TP53). These mutations provide hematopoietic stem cells with a competitive advantage, including an increased proliferative drive, self-renewal potential and/or capacity to evade death from cellular damage. Over time, these mutated HSCs thereby form a genetically distinct and expanded pool of differentiated blood cells that carry the same somatic variant. The prevalence of clonal hematopoiesis increases with age, and it affects more than 20-30% of the elderly population. A growing body of evidence suggests a self-perpetuating circle of inflammation and clonal expansion as cause and result of CHIP. However, the various factors underlying heterogeneity of CHIP-associated diseases remain poorly defined, also considering the observation that the vast majority of affected individuals do not develop CVD or HM and remain ostensibly healthy for many years. Overall, the lack of recognizable factors that predict the precise risk of a benign or more pathological outcome and potential ability to intervene therapeutically presents a challenge for the clinical community.In light of these challenges, we aim to assess the contribution of the different layers, specifically genetic and non-genetic factors that contribute to the development of CH associated phenotypes. To achieve this, we will perform comprehensive single cell multi-omic characterizations in conjunction with mutation-based clonal readouts to decipher cellular states and predictive biomarkers that associate with distinct disease phenotypes at the cellular and genomic level in a cohort of CH. We aim to address the following specific questions: (i) how does a given somatic CH mutation influence transcriptomic programs in relation to cell identity? (ii) Do individuals with CH show altered accessible chromatin states and heterogeneity of peripheral blood myeloid cells? (iii) Can different genomic states be characterized in the stem cell compartment of individuals with CH and do they differ with respect to various CH-associated diseases?

不确定电位克隆造血（CHIP）是一种以造血干细胞（hsc）获得体细胞突变为特征的衰老相关状态，与心血管疾病（CVD）、血液系统恶性肿瘤（HM）和全因死亡率的风险增加有关。chip相关突变影响恶性肿瘤相关基因，大致分为三大类基因，包括表观遗传调控因子（如DNMT3A、TET2、ASXL1）、剪接体（如SF3B1）和DNA损伤基因（如PPM1D、TP53）。这些突变为造血干细胞提供了竞争优势，包括增加的增殖驱动、自我更新潜力和/或逃避细胞损伤死亡的能力。随着时间的推移，这些突变的造血干细胞因此形成了一个遗传上独特的、扩大的、携带相同体细胞变异的分化血细胞池。克隆造血的患病率随着年龄的增长而增加，影响了20-30%以上的老年人群。越来越多的证据表明，自我延续的炎症和克隆扩增循环是CHIP的原因和结果。然而，chip相关疾病异质性的各种潜在因素仍然不明确，也考虑到绝大多数受影响的个体不会发展为CVD或HM，并且多年来表面上保持健康。总的来说，缺乏可识别的因素来预测良性或更多病理结果的精确风险和潜在的干预治疗能力，这对临床社区来说是一个挑战。鉴于这些挑战，我们的目标是评估不同层的贡献，特别是遗传和非遗传因素，有助于CH相关表型的发展。为了实现这一目标，我们将结合基于突变的克隆读数进行全面的单细胞多组学表征，以破译细胞状态和与CH队列中不同疾病表型在细胞和基因组水平相关的预测性生物标志物。我们的目标是解决以下具体问题：(i)给定的体细胞CH突变如何影响与细胞身份相关的转录组学程序？（ii） CH患者是否表现出可接近染色质状态的改变和外周血髓细胞的异质性？（iii）在CH患者的干细胞区室中，不同的基因组状态是否具有特征？它们在各种CH相关疾病中是否存在差异？