PROJECT SUMMARY

The identification of recurrent heterozygous hot-spot mutations in spliceosome genes SF3B1, SRSF2, and U2AF1 in patients with myelodysplastic syndromes (MDS) suggest a causal link between dysregulated pre-mRNA splicing and MDS pathogenesis. Expression of mutant splicing factors in vivo results in aberrant hematopoiesis that resemble MDS-like phenotypes due to functional alterations to pre-mRNA splicing. In addition, spliceosome-mutant cells are uniquely dependent on wildtype splicing function for survival, and co-expression of multiple mutant splicing factors results in synthetic lethality. This unique vulnerability represents a potential therapeutic strategy for spliceosome-mutant MDS, and this concept is currently under clinical investigation in MDS and leukemia patients. We recently demonstrated that spliceosome mutations, despite imparting distinct effects on gene expression and global RNA splicing, converge on hyperactive innate immune pathways through mis-splicing of signalling intermediates. Specifically, mutations in SF3B1 and SRSF2 directly alter splicing of MAP3K7 and Caspase-8 mRNAs, respectively, which result in enhanced NF-κB signalling. Based on these observations, we hypothesize that hyperactive innate immune activation is a unifying feature downstream of splicing factor mutations, and targeting aberrant immune signalling represents an important therapeutic strategy for spliceosome-mutant MDS.