Understanding the effect of mutations on cell behaviour in blood disorders through mathematical modelling and computational analysis

通过数学建模和计算分析了解突变对血液疾病细胞行为的影响

• 批准号: 2887435
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 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=studentship-2887435
• 关键词: Understanding; effect; mutations; cell; behaviour

Clonal expansion is particularly well studied in haematopoiesis, the production of blood cells. Clonal haematopoiesis (CH) is the expansion of mutations in haematopoietic stem cells (HSCs) that become detectable in blood or bone marrow of healthy aged individuals. More than 10% of the population over 65 years of age are affected by CH. CH is associated with increased risk for all- cause mortality, heart disease and ischaemic stroke. In 2022, CH has been recognised by the World Health Organization as a precursor myeloid disease state.CH constitutes a known risk factor for myelodysplastic syndromes (MDS), a group of blood cancers in which the maturation of blood stem cells in the bone marrow and their downstream production of differentiated blood cells is impaired. Mutations in spliceosome components, with SF3B1 as one of the most common events, play a significant role in driving clonal expansion and disease progression. Additionally, SF3B1 is a particularly interesting genetic driver due to its dual risk profile, constituting a protective event in MDS with ring sideroblasts (MDS-RS) and yet having a dismal prognosis when co- occurring in MDS with 5q deletion. The reasoning for these distinct effects and the role of different SF3B1 mutations in MDS expansion and progression are currently unknown.Risk prognosis is currently calculated as part of a diagnostic sequencing approach, with few studies centred on what factors drive clonal expansion over time. Being able to predict the clonal expansion of different mutations and understanding how co-mutations interact to modify disease risk could facilitate monitoring of MDS in individuals for the stratification of risk. More research is required to determine the mechanisms by which certain clones can outcompete others in the bone marrow and blood production.The Schumacher group has recently shown that mutations in different genes can have different expansion rates. This insight was enabled by the availability of longitudinal sequencing data from healthy aged individuals in combination with mathematical models of clonal expansion to make sense of such data. We now plan to apply this approach to quantify and understand the clonal expansion of SF3B1 mutations in MDS. As MDS with SF3B1 mutations are typically lower risk they are closer to the pre-malignant status of CH than other blood malignancies and therefore our methods may be applicable with only small modifications.The Hellström Lindberg group has established a well-annotated biobank of >1200 consecutive patients with MDS and related disorders. One focus of the group lies on MDS with mutations in the gene SF3B1, for which they do serial sampling over time. These data provide the ideal test-bed for extending theapplicability of recent mathematical models, guided by the clinical expertise of the Hellström Lindberg group. The group has also established a 3D culture system to study the clonal expansion of patient-derived cells with known mutations in vitro. We will systematically quantify the kinetics and variability of expansion of selected SF3B1 mutations. This will serve as validation of the in vivo findings and enable the further development of mathematical models to include different potential mechanisms of clonal expansion, the predictions of which can be tested experimentally.Aims1. Adapt mathematical models of clonal haematopoiesis to make them applicable to data from low risk MDS patients.2. Test whether rate of clonal expansion of SF3B1 mutations is specific to the mutational variant, hotspot location within the gene, or other factors (e.g., from clinical metadata).3. Verify differences in clonal expansion using 3D culture system and quantify variability of kinetics.4. Adapt mathematical models to make them applicable to in vitro data from 3D culture system.5. Determine the mechanism of how SF3B1 mutations cause clonal expansion using a combination of in vitro experiments and mathematical models.

克隆膨胀在血细胞的产生中尤其深入研究。克隆造血（CH）是造血干细胞（HSC）突变的扩展，这些突变在健康老年人的血液或骨髓中可检测到。 65岁以上的人口中，超过10％受CH的影响。 CH与所有引起的死亡率，心脏病和缺血性中风的风险增加有关。 CH在2022年被世界卫生组织认识到我们是髓样疾病的前体状态。CH构成了骨髓增生综合症（MDS）的已知危险因素，这是一组血液癌，其中骨髓中血干细胞的成熟及其下游血细胞的下游产生受损。 SF3B1作为最常见的事件之一的剪接组成分中的突变在推动克隆扩张和疾病进展中起着重要作用。此外，由于其双重风险概况，SF3B1是一个特别有趣的遗传驱动因素，构成了带有环粒细胞（MDS-RS）的MDS中受保护的事件，但在MDS在MDS（5Q删除的MDS）中共发生时，进展却令人沮丧。目前尚不清楚这些独特作用的推理以及不同SF3B1突变在MDS扩展和进展中的作用。当前将风险进展计算为诊断测序方法的一部分，而很少有研究集中在哪些因素驱动克隆延伸的因素随时间延伸。能够预测不同突变的克隆扩张，并了解共突变如何相互作用以改变疾病风险，可以促进对个体中MDS监测风险分层的监测。需要更多的研究来确定某些克隆在骨髓和血液产生中胜过其他克隆的机制。舒马赫组最近表明，不同基因的突变可能具有不同的膨胀率。通过从健康老年人的纵向测序数据以及克隆扩展模型结合使用以理解此类数据的数学模型，从而实现了这种见解。现在，我们计划采用这种方法来量化和了解MDS中SF3B1突变的克隆扩张。由于具有SF3B1突变的MD通常是较低的风险，因此与其他血液恶性肿瘤相比，它们更接近CH的恶性前状态，因此我们的方法可能仅适用于小型修改。HellströmLindbergGroup已建立了一个众多良好的生物库，> 1200个> 1200个连续的MDS和相关异常。该组的一个重点在于具有突变SF3B1突变的MD，它们会随着时间的推移进行串行采样。这些数据为在HellströmLindbergGroup的临床专业知识的指导下提供了理想的测试床，用于扩展最近的数学模型的适用性。该小组还建立了一个3D培养系统，以研究具有已知突变的患者衍生细胞的克隆扩张。我们将系统地量化选定SF3B1突变扩展的动力学和变异性。这将作为对体内发现的验证，并使数学模型的进一步发展能够包括克隆扩张的不同潜在机制，可以通过实验测试其预测。IAMS1。适应克隆造血的数学模型，使其适用于低风险MDS患者的数据。2。测试SF3B1突变的克隆膨胀速率是否特定于突变变体，基因内的热点位置或其他因素（例如，来自临床元数据）。3。使用3D培养系统验证克隆扩张的差异并量化动力学的变异性4。适应数学模型，使其适用于3D培养系统的体外数据5。确定SF3B1突变如何使用体外实验和数学模型的组合引起克隆扩张的机制。