Splicing and inflammatory dysregulation in myelodysplastic syndromes at the single-cell level

Susann Winter, TUD, University Hospital Dresden; Shahram Kordasti, King’s, Comprehensive Cancer Centre

Research area: Haematology

Myelodysplastic syndromes (MDS) represent a heterogeneous group of haematological diseases that manifest themselves through ineffective blood cell maturation in the bone marrow. Mutations in splicing factors are commonly seen in MDS, yet the specific inflammatory pathway activated by mis-splicing have not been fully elucidated. Recent data suggests that mutations in splicing factors SF3B1 and U2AF1 induce an overactive form of the enzyme IRAK-4-L that is involved in multiple inflammatory signalling pathways. Published RNA-seq datasets on SF3B1 suggest that there are much broader splicing abnormalities in pro-inflammatory cytokine genes. Thus, while IRAK-4-L facilitates the expression of these genes, the induced genes themselves may be subject to mis-splicing with implications for the overall inflammatory outcome.

The project will combine the expertise of Shahram Kordasti’s group in the analysis of large single-cell datasets on the immunobiology of haematological malignancies and Susann Winter’s in the immune dysregulation of MDS. Both partners want to investigate inflammatory splicing signatures in order to aid future stratification of patients for novel therapeutic approaches.