Determinants of Clonal Fitness in SF3B1-Mutant Clonal Haematopoiesis

About the project

About the Project A 2027 Crick PhD project with Dominique Bonnet. Project background and description Background Clonal haematopoiesis (CH) is an age-associated condition in which haematopoietic stem cell (HSC) clones carrying somatic mutations acquire a competitive advantage and progressively expand [1]. Among recurrent CH-associated mutations, SF3B1, which encodes a core component of the U2 spliceosome, is one of the most frequently mutated spliceosome genes. Unlike the common CH drivers DNMT3A, TET2 and ASXL1, which primarily alter epigenetic regulation, SF3B1 mutations disrupt RNA splicing, resulting in widespread changes in gene expression, altered erythropoiesis and inflammation. Although SF3B1 mutations account for only 1 to 3% of CH cases, they are strongly associated with ageing and carry a significantly higher risk of progression to myeloid neoplasms [2]. Despite extensive characterization of SF3B1-induced splicing defects, the mechanisms underlying clonal expansion remain poorly understood. In particular, it is unknown how aberrant splicing translates into increased HSC fitness, why some SF3B1-mutant clones remain stable while others rapidly expand, and how frequent co-mutations in genes such as DNMT3A and TET2 influence this process. Furthermore, although SF3B1-mutant clones preferentially expand in older individuals, the contribution of the ageing bone marrow niche has never been directly investigated. We hypothesize that the competitive advantage of SF3B1-mutant HSCs is determined by the combined effects of aberrant RNA splicing, epigenetic context, cooperating mutations and the ageing bone marrow microenvironment. Research Aims Aim 1. Define the molecular mechanisms linking SF3B1 mutations to enhanced HSC fitness. Identify the transcriptional, splicing and cellular pathways that promote competitive advantage and altered stem cell function. Aim 2. Determine how epigenetic context and cooperating mutations regulate SF3B1-driven clonal expansion. Investigate how mutations in epigenetic regulators, such as DNMT3A and TET2, and mutation order influence clonal fitness and disease progression. Aim 3. Establish the role of the ageing bone marrow niche in SF3B1-mutant clonal expansion. Develop physiological models to determine how age-related changes in the bone marrow microenvironment regulate mutant HSC competition and expansion. The project is relying on the potential to genetically edit human HSPCs and select for SF3B1 mutant clones. This is possible via the use of iPS lines and the development of protocols that can generate induced human haematopoietic stem cells with repopulating capacity in vivo when injected into immunodeficient mice [3]. Furthermore, preliminary data from our group has provided evidence that TET.2 mutant iHSCs behave similarly to gene editing adult HSC, reinforcing the utility of this model system [4]. In addition, the project will take advantage of our humanised niche model [5] which allowed us to investigate the role of ageing of the bone marrow niche on SFB31 selection. Expected outcomes and impact This project will define the intrinsic and extrinsic mechanisms that determine the fitness of SF3B1-mutant HSCs, providing the first integrated analysis of RNA splicing, epigenetic state and the ageing bone marrow niche in clonal haematopoiesis. The work will generate physiologically relevant experimental models, identify pathways that drive clonal expansion, and uncover biomarkers and therapeutic targets to predict and prevent progression from SF3B1-mutant clonal haematopoiesis to myeloid malignancies. By moving beyond mutation-centric models, this research will provide a new framework for understanding age-associated clonal evolution and malignant transformation. Candidate background Candidates with a background in biomedical sciences, and/or with knowledge and experience in stem cell biology, gene editing and/or culture of iPS are encouraged to apply. Lab-specific question Looking at the research undertaken in our lab, what aspect would you be most interested in exploring further? Drawing on your own research experience, what perspective, skill or approach would you bring to investigating it?

Research areas