Splicing dysregulation and haemopoietic disease

Splicing of pre-mRNA occurs in all eukaryotic cells to ensure correct gene expression. Although it is a ubiquitous process it arises differently in different cell types to achieve diverse biological outcomes specific to a particular cell type. This is highlighted by the phenotypes generated by splicing factor mutations in human diseases. These are remarkably specific, often leading to degenerative disease and/or cancer in a few specific tissues, even when the mutations are congenital. Myelodysplastic syndromes (MDS) are a common, heterogeneous group of haemopoietic stem cell disorders characterised by peripheral cytopenias and a predisposition to transform into secondary acute myeloid leukaemia. Recurrent splicing factor mutations are prevalent in MDS, implicating the splicing machinery in MDS pathogenesis and prognostic significance. We aim to better understand the paradox of ubiquity versus tissue specificity in splicing using granulopoiesis as a paradigmatic biological and haematological process susceptible to splicing regulation in both health and disease.