Understanding the Role of Adipogenesis in Clonal Haematopoiesis and Progression to MDS

Clonal Haematopoiesis (CH) is an age-associated expansion of mutated Haematopoietic stem cells (HSCs) within the bone marrow (BM). CH is considered a pre-malignant state with a risk of progressing to haematological malignancies such as myelodysplastic syndrome (MDS), which poses a 25% risk of developing into acute myeloid leukaemia (AML). HSCs reside in specialised niches within the bone marrow (BM) where various cell types such as mesenchymal stromal cells (MSCs) and adipocytes play a role in regulating HSC function. However, the mechanisms responsible have yet to be fully elucidated. Our preliminary findings reveal a pro-adipogenic BM phenotype in CH and a novel pro-adipogenic MSC subset which is increased in MDS. We hypothesise that adipogenesis plays a vital role in promoting CH and the development of MDS. This proposal aims to understand how adipocytes and this novel MSC are implicated in clonal haematopoiesis. Nuclei RNA sequencing and spatial transcriptomics will be employed to identify CH-specific HSC signalling interactions in the BM. Furthermore, the contribution of these adipocyte-HSC signalling interactions will be investigated using conditional knock-out mouse models. These aims will provide critical insight into the mechanisms underlying CH and MDS with future implications for studying other age-associated disorders such as leukaemia.