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.

克隆扩增在造血作用中得到了特别深入的研究，克隆造血 (CH) 是指造血干细胞 (HSC) 突变的扩增，这些突变可在健康老年人的血液或骨髓中检测到。 65 岁以上人群受到 CH 的影响，CH 与全因死亡率、心脏病和缺血性中风的风险增加有关。被世界卫生组织认定为前体骨髓疾病状态。CH 是骨髓增生异常综合征 (MDS) 的已知危险因素，MDS 是一组血癌，其中骨髓中造血干细胞的成熟及其下游分化血液的产生剪接体成分的突变（其中 SF3B1 是最常见的事件之一）在驱动克隆扩张和疾病进展中发挥着重要作用。由于其双重风险特征，构成环状铁粒幼细胞 (MDS-RS) 的 MDS 中的保护性事件，但当与 5q 缺失同时发生的 MDS 中时，预后不佳。这些不同效应的原因以及不同 SF3B1 突变的作用。 MDS 扩增和进展的影响目前尚不清楚。风险预后目前作为诊断测序方法的一部分进行计算，很少有研究关注随着时间的推移驱动克隆扩增的因素。不同的突变以及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的监测，以进行风险分层，以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，不同基因的突变可能具有不同的扩增率，这一见解是通过健康老年人的纵向测序数据与克隆扩增的数学模型相结合来实现的，我们现在计划对这些数据进行理解。应用这种方法来量化和理解MDS 中 SF3B1 突变的克隆扩展由于具有 SF3B1 突变的 MDS 风险通常较低，因此与其他血液恶性肿瘤相比，它们更接近 CH 的癌前状态，因此我们的方法只需稍作修改即可适用。Hellström Lindberg 小组建立了一个注释良好的生物库，其中包含超过 1200 名患有 MDS 和相关疾病的连续患者，该小组的一个重点是具有 SF3B1 基因突变的 MDS，他们对此进行了连续采样。这些数据为扩展最新数学模型的适用性提供了理想的测试平台，在 Hellström Lindberg 小组的临床专业知识的指导下，该小组还建立了一个 3D 培养系统来研究患者来源的细胞的克隆扩增。我们最终将量化所选 SF3B1 突变的动力学和变异性，这将作为体内研究结果的验证，并能够进一步开发数学模型，以包括克隆扩增的不同潜在机制、预测。这可以目的 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. 测试 SF3B1 突变的克隆扩展率是否特定于突变变异、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增的差异并量化动力学的变异性。4. 调整数学模型以使其适用于体外数据。来自3D培养系统。5.结合体外实验和数学模型确定SF3B1突变如何引起克隆扩增的机制。