Mutations in spliceosome genes and therapeutic opportunities in myeloid malignancies

Abstract

Since the discovery of RNA splicing more than 40 years ago, our comprehension of the molecular events orchestrating constitutive and alternative splicing has greatly improved. Dysregulation of pre‐mRNA splicing has been observed in many human diseases including neurodegenerative diseases and cancer. The recent identification of frequent somatic mutations in core components of the spliceosome in myeloid malignancies and functional analysis using model systems has advanced our knowledge of how splicing alterations contribute to disease pathogenesis. In this review, we summarize our current understanding on the mechanisms of how mutant splicing factors impact splicing and the resulting functional and pathophysiological consequences. We also review recent advances to develop novel therapeutic approaches targeting splicing catalysis and splicing regulatory proteins, and discuss emerging technologies using oligonucleotide‐based therapies to modulate pathogenically spliced isoforms.

Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues

“…U2AF1 is an U2 auxiliary factor protein involved in recognizing the 3′ boundary of introns at the AG splice site acceptor dinucleotide [ 85 ]. Its role in determining exon boundaries is crucial for the selection of spliced exons [ 86 ].…”

The Role of cis- and trans-Acting RNA Regulatory Elements in Leukemia

“…Mutations in splicing factor genes are especially common for adult chronic myeloid and lymphoblastic leukemia [ 36 ]. Conversely, somatic mutations in splicing factors were not typical for pediatric B-ALL.…”

Innovative Therapeutic and Delivery Approaches Using Nanotechnology to Correct Splicing Defects Underlying Disease

“…This number is likely an underestimate, since most of the reported mutations have been identified by genomic DNA sequencing without consideration that missense, nonsense and synonymous changes can affect splicing, as reported previously for coagulation factor IX exon 5 ( Tajnik et al, 2016 ). It has been estimated that up to 50% of mutations that lead to heritable disease occur as a result of errors in the RNA splicing process or its regulation ( Lopez-Bigas et al, 2005 ; Taylor and Lee, 2019 ). While we wait for functional testing of predicted mutations, the development of new and effective predictive algorithms for splicing effect analysis is critical ( Anna and Monika, 2018 ).…”

“…These findings suggest a potential relationship between certain spliceosome gene mutations and carcinogenesis. For MDS, SF3B1 , SRSF2 , U2AF1 , and ZRSR2 are the four most commonly mutated splicing factor genes, although mutations in other splicing factor genes have also been observed ( Taylor and Lee, 2019 ). Although the underlying mechanisms and contributions of splicing factors in cancer pathogenesis have not been elucidated, and although more work is needed to understand the splicing alterations observed in cancer cells, these data identify novel opportunities for development of splicing-based cancer therapies.…”