Understanding the effect of mutations on cell behaviour in blood disorders through mathematical modelling and computational analysis
Lead Research Organisation:
University of Edinburgh
Department Name: Sch of Molecular. Genetics & Pop Health
Abstract
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 the
applicability 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.
Aims
1. 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.
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 the
applicability 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.
Aims
1. 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.
Organisations
People |
ORCID iD |
| Linus Schumacher (Primary Supervisor) | |
| Cameron Kerr (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/W006804/1 | 01/10/2022 | 30/09/2028 | |||
| 2887435 | Studentship | MR/W006804/1 | 01/09/2023 | 28/02/2027 | Cameron Kerr |