Elucidating the Immune Landscape in Clonal Haematopoiesis of Indeterminate Potential and Progression to Haematological Malignancy

阐明不确定潜力的克隆造血过程中的免疫景观和血液恶性肿瘤的进展

• 批准号: MR/X001423/1
• 负责人: Ellen Nuttall Musson
• 金额: $ 37.4万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX001423%2F1
• 关键词: Elucidating; Immune; Landscape; Clonal; Haematopoiesis

Clonal Haematopoesis of Indeterminant Potential (CHIP) is a term used to describe the presence of blood cancer-causing genetic alterations in otherwise normal blood cells. CHIP is a common finding in normal people as part of the ageing process. It is seen in 1 in 10 people over 70 years. The presence of CHIP increases the risk of blood cancers, such as myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) , as well as heart disease. However, this increase in risk is relatively modest. Therefore, it is important to understand which individuals with CHIP have the greatest risk of these more severe conditions and why.The goal of being able to identify CHIP and those at greatest risk of evolving into cancer is to find ways to avoid or delay this happening. This is vitally important in MDS and AML, especially in older people, as due to the toxic nature of the treatment these conditions are incurable. It is relatively straight forward to test patients for CHIP, however, we do not know much about which patients will progress to blood cancer. This vital knowledge is a big gap in our understanding of CHIP because we cannot provide appropriate further information to affected patients. An area of increasing interest in cancer is understanding how our own bodies immune system reacts to cancer cells (termed cancer immunology). Cancer cells commonly develop methods of hiding themselves from the immune system to help them grow. New treatments have been developed in the past few years that can help the immune system to see and destroy cancer cells, or create artificially modified immune cells that target the cancer cells specifically. Effective immune responses against cancer cells (particularly in 'T-cells'), are the most important defence that the body has against the development of cancer. Interestingly, T-cell responses directed against CHIP/AML-associated mutations have been found. However, the role of the immune system in helping to control CHIP, and its progression to MDS/AML are not clear. We think that active immunity towards CHIP cells may protect patients from developing MDS/AML. The goal of this project therefore is to understand in detail the immune cells and how they work in patients with CHIP. We will investigate if CHIP-specific T-cell responses can be identified and if these predict progression from CHIP to MDS/AML. This project benefits from access to a unique resource: the English Longitudinal Study of Ageing (ELSA). ELSA is a long-running study into ageing (since 2002). As part of the study, participants are interviewed about their health and blood samples taken every other year. It is therefore perfectly placed to investigate CHIP and its progression/complications over time. We will screen these samples for mutations to identify individuals with CHIP and assess how the CHIP progresses over time. In conjunction with ELSA, will with then collect new blood samples from specific individuals with CHIP for more detailed analysis of the immune cells.Using these samples and the world-class expertise in cancer immunology in the host institution, we will look at the range of different cells in the immune system in CHIP. Particularly we will assess the types and function of T-cells and how these change with CHIP progression. We will also look at other types of immune cells in the blood, that may be altered by CHIP. We propose a particularly exciting and novel experiment using mutation-specific markers to separate out the blood cells carrying the CHIP mutations to compare them to normal cells. Given the poor prognosis of MDS/AML in older people, the long-term aim of this research is to improve understanding of the biology of CHIP and its progression to MDS/AML, to progress the field towards strategies aimed at modifying the risk of developing of blood cancer and other CHIP-associated health problem.

克隆性不确定电位造血（CHIP）是一个术语，用于描述在其他正常血细胞中存在引起血癌的遗传改变。作为衰老过程的一部分，CHIP在正常人中很常见。在70岁以上的人群中，每10人中就有1人患此病。CHIP的存在增加了血癌的风险，如骨髓增生异常综合征（MDS）和急性髓性白血病（AML），以及心脏病。然而，这种风险的增加是相对温和的。因此，了解哪些CHIP患者患这些更严重疾病的风险最大及其原因是很重要的。能够识别CHIP和那些最有可能发展成癌症的人的目标是找到避免或延缓这种情况发生的方法。这对于MDS和AML至关重要，特别是在老年人中，因为由于治疗的毒性，这些疾病是无法治愈的。对患者进行CHIP检测相对简单，然而，我们不太清楚哪些患者会发展为血癌。这一至关重要的知识是我们对CHIP理解的一个巨大差距，因为我们无法向受影响的患者提供适当的进一步信息。人们对癌症越来越感兴趣的一个领域是了解我们自己身体的免疫系统对癌细胞的反应（称为癌症免疫学）。癌细胞通常会发展出躲避免疫系统的方法来帮助它们生长。在过去的几年里，新的治疗方法已经被开发出来，可以帮助免疫系统发现并摧毁癌细胞，或者创造出专门针对癌细胞的人工修饰的免疫细胞。针对癌细胞（特别是“t细胞”）的有效免疫反应是身体对抗癌症发展的最重要防御。有趣的是，已经发现针对CHIP/ aml相关突变的t细胞反应。然而，免疫系统在帮助控制CHIP及其向MDS/AML进展中的作用尚不清楚。我们认为针对CHIP细胞的主动免疫可能保护患者免受MDS/AML的发展。因此，该项目的目标是详细了解免疫细胞及其在CHIP患者中的作用。我们将研究是否可以识别CHIP特异性t细胞反应，以及这些反应是否可以预测从CHIP到MDS/AML的进展。这个项目得益于一个独特的资源：英国老龄化纵向研究（ELSA）。ELSA是一项关于老龄化的长期研究（从2002年开始）。作为研究的一部分，参与者接受了关于他们健康状况的采访，并每隔一年采集一次血液样本。因此，随着时间的推移，它是研究CHIP及其进展/并发症的完美选择。我们将对这些样本进行突变筛选，以确定CHIP患者，并评估CHIP随时间的进展情况。结合ELSA，我们将从特定的CHIP患者身上收集新的血液样本，对免疫细胞进行更详细的分析。利用这些样本和宿主机构在癌症免疫学方面的世界级专业知识，我们将在CHIP中研究免疫系统中不同细胞的范围。特别是我们将评估t细胞的类型和功能以及它们如何随着CHIP的进展而变化。我们还将研究血液中可能被CHIP改变的其他类型的免疫细胞。我们提出了一个特别令人兴奋和新颖的实验，使用突变特异性标记分离出携带CHIP突变的血细胞，并将其与正常细胞进行比较。鉴于老年人MDS/AML预后不良，本研究的长期目标是提高对CHIP生物学及其向MDS/AML进展的理解，推动该领域制定旨在改变血癌发展风险和其他CHIP相关健康问题的策略。