Abstract Body

Mutations in RNA splicing factors are the single most common class of genomic alterations in patients with myelodysplastic syndromes (MDS) and also occur in the setting of clonal hematopoiesis which predates MDS for many patients. Splicing factor mutations serve as attractive therapeutic targets as they frequently occur as early initiating events, are present in dominant clones, and are found in cancers with few effective treatment options. Spliceosomal mutations in SF3B1, SRSF2 and U2AF1 typically harbor mutually-exclusive heterozygous mutations and co-expression of these mutations is intolerable to cells. Furthermore, several studies have shown that splicing mutant cells are preferentially dependent on wild-type spliceosome function with deletion of the wild-type allele in splicing factor mutant cancer cells leading to cell death across different cancer subtypes with mutations in SF3B1, SRSF2, or U2AF1. These data highlight the potential vulnerability of splicing factor mutant cells to global perturbations in splicing catalysis and provide a therapeutic rationale for targeting splicing to trigger cell death.

This presentation will discuss several means to therapeutically target splicing factor mutant MDS. These include small molecules which bind to the SF3b component of the spliceosome, RBM39 degrading compounds, small molecule inhibitors targeting U2AF splicing interactions, and a number of enzymes which place post-translational modifications on RNA splicing factors. For this latter category we will specifically discuss enzymatic inhibitors of CLK and DYRK kinases as well as PRMT inhibitors.

Beyond chemicals, this presentation will also discuss a suite of synthetic RNA species which are specifically recognized by mutant splicing factors to drive selective gene expression. We have harnessed this approach to selectively eliminate splicing factor mutant cells but also to identify drugs and proteins required by the mutant spliceosome.

Finally, research from our laboratories has identified that the most common spliceosomal mutations alter RNA recognition in a sequence-specific manner to cause widespread mis-splicing. This widespread production of mis-spliced mRNAs, many of which encode novel peptides, could result in high levels of neoantigen production. Indeed, our preliminary studies have identified such putative neoantigens that are generated via mis-splicing arising from oncogenic spliceosomal mutations, presented by MHC class I, and capable of stimulating a cytotoxic T cell response. This work will also be discussed.