Abstract
A growing number of large-scale genomic studies of cancer have uncovered mutations that drive cancer by perturbing co- and post-transcriptional regulation of gene expression. These include alterations that impact each phase of RNA processing, including splicing, transport, editing, and decay of messenger RNA. The discovery of these events illuminates a number of novel therapeutic vulnerabilities generated by aberrant RNA processing in cancer, several of which have progressed to clinical development.
Mutations in the spliceosomal genes SRSF2, U2AF1 and SF3B1 are commonly found in patients with leukemia and are among the most common class of genetic alterations in myelodysplastic syndromes (MDS), clonal hematopoiesis, and chronic lymphocytic leukemia (CLL). These mutations occur at highly restricted amino acid residues, are always heterozygous, and never co-occur with one another. Work from our group and others has identified that these mutations alter RNA splicing in a manner distinct from loss of function and drive development of aberrantly spliced mRNAs, a portion of which are required for disease maintenance.
In contrast to splicing factors affected by hotspot mutations, functional alterations induced by loss of functions in the RNA splicing factor ZRSR2 are less understood. Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles for the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections between minor introns, hematopoiesis, and cancers are unclear. These events will be discussed and provide novel insights into the role of mutant splicing factors in the pathogenesis of leukemia.