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.

克隆扩增在造血（血细胞的产生）中得到了很好的研究。克隆造血（CH）是在健康老年人的血液或骨髓中检测到的造血干细胞（hsc）突变的扩展。65岁以上人群中有超过10%的人患有慢性阻塞性肺病。慢性阻塞性肺病与全因死亡率、心脏病和缺血性中风的风险增加有关。2022年，CH被世界卫生组织认定为前驱髓系疾病状态。CH是骨髓增生异常综合征（MDS）的已知危险因素，MDS是一组血液癌症，其中骨髓中血液干细胞的成熟及其下游分化血细胞的产生受损。剪接体成分的突变，SF3B1是最常见的事件之一，在驱动克隆扩增和疾病进展中起着重要作用。此外，SF3B1是一个特别有趣的遗传驱动因素，由于其双重风险特征，它在MDS伴环状铁母细胞（MDS- rs）中构成保护事件，但在MDS伴5q缺失时却具有令人沮丧的预后。这些不同效应的原因以及不同的SF3B1突变在MDS扩展和进展中的作用目前尚不清楚。目前，风险预后的计算是诊断测序方法的一部分，很少有研究集中在哪些因素会随着时间的推移推动克隆扩增。能够预测不同突变的克隆扩增和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MDS的风险分层监测。需要更多的研究来确定某些克隆在骨髓和血液生产方面胜过其他克隆的机制。舒马赫小组最近表明，不同基因的突变可以有不同的扩展率。这一见解是通过健康老年人纵向测序数据的可用性以及克隆扩增的数学模型来理解这些数据而实现的。我们现在计划应用这种方法来量化和了解MDS中SF3B1突变的克隆扩增。由于伴有SF3B1突变的MDS通常风险较低，与其他血液恶性肿瘤相比，它们更接近于CH的恶性前状态，因此我们的方法可能只需要稍加修改即可适用。Hellström Lindberg集团已经建立了一个带有良好注释的生物库，其中包含了bb101200名MDS及相关疾病患者。该小组的一个重点是SF3B1基因突变的MDS，他们随着时间的推移进行了连续采样。这些数据提供了理想的试验台，以扩展最近的数学模型的适用性，由Hellström林德伯格集团的临床专业知识指导。该小组还建立了一个3D培养系统，用于研究体外已知突变的患者来源细胞的克隆扩增。我们将系统地量化选定SF3B1突变扩展的动力学和变异性。这将作为体内研究结果的验证，并使数学模型的进一步发展包括克隆扩增的不同潜在机制，其预测可以在实验中进行测试。1 .调整克隆造血的数学模型，使其适用于低风险MDS患者的数据。2 .检测SF3B1突变克隆扩增率是否与突变变异体、基因内热点位置或其他因素（如临床元数据）有关。利用三维培养系统验证克隆扩增的差异，并量化动力学变异。调整数学模型，使其适用于三维培养系统的体外数据。利用体外实验和数学模型相结合确定SF3B1突变引起克隆扩增的机制。