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Alternative pre-mRNA processing enables the production of distinct mRNA and protein isoforms from a single gene, thus greatly expanding the coding potential of eukaryotic genomes and fine-tuning gene expression programs. Splicing is carried out by the spliceosome, a complex molecular machinery which assembles step-wise on mRNA precursors in the nucleus of eukaryotic cells. In the last decade, exome sequencing technologies have allowed the identification of point mutations in genes encoding splicing factors as a recurrent hallmark of human cancers, with higher incidence in hematological malignancies. These mutations lead to production of splicing factors that reduce the fidelity of the splicing process and yield splicing variants that are often advantageous for cancer cells. However, at the same time, these mutations increase the sensitivity of transformed cells to splicing inhibitors, thus offering a therapeutic opportunity for novel targeted strategies. Herein, we review the recent literature documenting cancer-associated mutations in components of the early spliceosome complex and discuss novel therapeutic strategies based on small-molecule spliceosome inhibitors that exhibit strong anti-tumor effects, particularly against cancer cells harboring mutations in spliceosomal components.

Somatic Mutations in Core Spliceosome Components Promote Tumorigenesis and Generate an Exploitable Vulnerability in Human Cancer