Clinical utility and biological impact of platelet-restricted clonal haematopoiesis

该项目旨在了解异常扩张的血液干细胞、血凝块（静脉血栓栓塞）和缺血性心脏病之间的联系。血液干细胞具有自我更新和发育成所有成熟血细胞的能力，如白细胞（对抗感染）和血小板（血液凝固所必需的）。随着年龄的增长，DNA复制错误（突变）是后天获得的，但其中大多数是无关紧要的。然而，有时这些干细胞获得突变，使它们的后代具有生存优势，它们的数量也会增加。这种扩大的种群被称为克隆；这个过程被称为克隆造血。正如你所料，克隆造血在老年人群中更为常见，在70岁以上的人群中约有10-20%的人存在克隆造血。克隆造血与患血癌的风险增加10倍有关。然而，最近的研究表明，它与血液凝块和心脏病的风险增加两倍有关。扩增克隆与血栓/心脏病之间的联系的潜在原因尚不清楚，但它被认为与伴随衰老的慢性炎症交织在一起。据认为，由于异常的免疫反应，扩大的克隆与炎症反应有关，这是已知的促成这些疾病。检测血块和心脏病患者体内的克隆造血（一种“癌前”状态）可能会带来防止血癌进展的新方法，并降低进一步发生血块或心脏病的风险。有证据表明，许多干细胞的后代只对血小板谱系有贡献，尽管它们仍然能够成为任何类型的血细胞。此外，这种“血小板偏倚”似乎随着年龄的增长而更多地发生。检测干细胞克隆的标准技术是在成熟的白细胞中寻找特定的突变，但我们实验室的初步工作表明，在70岁以上的人中，有10%的人只在血小板中检测到克隆，而在白细胞中检测不到；这是一个全新的发现。我们还不知道这些偏向血小板的干细胞克隆是否与血凝块和心脏病有关，因为所有证明这些联系的证据都是使用标准的白细胞检测方法。血小板是正常血液凝固的关键，与炎症和癌症有关，因此我们假设血小板偏向干细胞克隆在这一关联中起着重要作用。为了调查这一点，我们的目标是：1。确定血小板偏倚性克隆造血与静脉血栓栓塞和心脏病之间是否存在关联。我们将在有血栓和心脏病的患者中筛查血小板偏向性CH的存在。研究血小板偏向性克隆造血驱动血栓和心脏病增加的机制。这将包括功能性研究，如血小板活化研究，以确定血小板偏置CH是否与异常血小板活化有关。我们还将分析5-10名患者的骨髓（干细胞的来源），以检查这些异常血小板的细胞起源。3. 寻找与血小板偏向性克隆造血特异性相关的新突变，以防这些突变与目前公认的引起白细胞克隆造血的突变不同。标准CH检测方法。计划工作的一个关键目标是发展克隆造血的专业知识，这将支持新的CH诊所（已在美国设立，但未在英国设立）。一旦被发现，这些患者就会被告知如何减少与此类克隆相关的风险。通过我们在了解这些关联机制方面的工作，我们希望确定药物开发的靶点，以降低这些患者疾病发展的风险。

This project aims to understand the links between abnormally expanded blood stem cells, blood clots (venous thromboembolism) and ischemic heart disease. Blood stem cells have the capacity to self-renew and to develop into all the mature blood cells, such as white blood cells (that fight infection) and platelets (essential for blood clotting). As we age, DNA copying mistakes (mutations) are acquired, but most of these are inconsequential. However, sometimes these stem cells acquire mutations that give their progeny a survival advantage and their numbers expand. Such expanded populations are referred to as a clone; the process is termed clonal haematopoiesis. As you might expect, clonal haematopoiesis is found more frequently in the ageing population, in around 10-20% of people over 70 years. Clonal haematopoiesis is associated with a 10-fold increased risk of developing blood cancers. However, it has more recently been shown to be associated with a twofold increased risk of blood clots and heart disease. The underlying cause of this association between expanded clones and blood clots/heart disease is unknown, but it is thought to be entwined with the chronic inflammation which accompanies aging. It is thought that, due to abnormal immune responses, the expanded clone is associated with an inflammatory response which is known to contribute to these diseases. The detection of clonal haematopoiesis, a 'pre-cancer' state, in people with blood clots and heart disease could lead to new ways to prevent progression to blood cancer, as well as reduce risk of further blood clots or heart disease.There is evidence that many stem cells have offspring which only contribute to the platelet lineage, although they are still capable of becoming any type of blood cell. Furthermore, this 'platelet-bias' seems to occur more with advancing age. The standard techniques to detect stem cell clones look for specific mutations in mature white blood cells, but preliminary work in our lab shows that 10% of people over the age of 70 have clones detectable only in platelets as opposed to white blood cells; this is an entirely new finding. We don't yet know if these platelet-biased stem cell clones have links with blood clots and heart disease, as all of the evidence proving these links have used the standard white blood cell detection methods. Platelets are key to normal blood clotting and are implicated in inflammation and cancer, so we hypothesise that platelet-biased stem cell clones play an important role in this association. To investigate this, we aim:1. To determine if there is an association between platelet-biased clonal haematopoiesis and venous thromboembolism and heart disease. We will screen for the presence of platelet-biased CH in patients with blood clots and heart disease.2. To investigate the mechanisms by which platelet-biased clonal haematopoiesis drives increased blood clots and heart disease. This will include functional studies such as platelet activation studies, to determine if platelet-biased CH is associated with abnormal platelet activation. We will also analyse the bone marrow (where stem cells are made) of 5-10 patients to examine the cellular origins of these aberrant platelets. 3. To look for novel mutations that are specifically associated with platelet-biased clonal haematopoiesis, in case these are different to the mutations currently recognised to cause clonal haematopoiesis in white blood cells ie. the standard CH detection method.A key aim of the planned work is to develop expertise in clonal haematopoiesis which would support new CH clinics (already set up in the US but not the UK). Once detected, these patients could be counselled on how to reduce the risks associated with such clones. Through our work in understanding the mechanisms of these associations, we hope to identify targets for drug development to reduce the risk of diseases developing in these patients.