Article ; Online: Splicing factor mutations in the myelodysplastic syndromes: Role of key aberrantly spliced genes in disease pathophysiology and treatment.
Advances in biological regulation
2022 Volume 87, Page(s) 100920
Abstract: Mutations of splicing factor genes (including SF3B1, SRSF2, U2AF1 and ZRSR2) occur in more than half of all patients with myelodysplastic syndromes (MDS), a heterogeneous group of myeloid neoplasms. Splicing factor mutations lead to aberrant pre-mRNA ... ...
| Abstract | Mutations of splicing factor genes (including SF3B1, SRSF2, U2AF1 and ZRSR2) occur in more than half of all patients with myelodysplastic syndromes (MDS), a heterogeneous group of myeloid neoplasms. Splicing factor mutations lead to aberrant pre-mRNA splicing of many genes, some of which have been shown in functional studies to impact on hematopoiesis and to contribute to the MDS phenotype. This clearly demonstrates that impaired spliceosome function plays an important role in MDS pathophysiology. Recent studies that harnessed the power of induced pluripotent stem cell (iPSC) and CRISPR/Cas9 gene editing technologies to generate new iPSC-based models of splicing factor mutant MDS, have further illuminated the role of key downstream target genes. The aberrantly spliced genes and the dysregulated pathways associated with splicing factor mutations in MDS represent potential new therapeutic targets. Emerging data has shown that IRAK4 is aberrantly spliced in SF3B1 and U2AF1 mutant MDS, leading to hyperactivation of NF-κB signaling. Pharmacological inhibition of IRAK4 has shown efficacy in pre-clinical studies and in MDS clinical trials, with higher response rates in patients with splicing factor mutations. Our increasing knowledge of the effects of splicing factor mutations in MDS is leading to the development of new treatments that may benefit patients harboring these mutations. |
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| MeSH term(s) | Humans ; RNA Splicing Factors/genetics ; DNA, Recombinant/metabolism ; DNA, Recombinant/pharmacology ; DNA, Recombinant/therapeutic use ; Interleukin-1 Receptor-Associated Kinases/genetics ; Interleukin-1 Receptor-Associated Kinases/metabolism ; Interleukin-1 Receptor-Associated Kinases/pharmacology ; Splicing Factor U2AF/genetics ; Splicing Factor U2AF/metabolism ; Myelodysplastic Syndromes/genetics ; Spliceosomes/genetics ; RNA Splicing ; Mutation |
| Chemical Substances | RNA Splicing Factors ; DNA, Recombinant ; Interleukin-1 Receptor-Associated Kinases (EC 2.7.11.1) ; Splicing Factor U2AF |
| Language | English |
| Publishing date | 2022-10-04 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2667413-0 |
| ISSN | 2212-4934 ; 2212-4926 |
| ISSN (online) | 2212-4934 |
| ISSN | 2212-4926 |
| DOI | 10.1016/j.jbior.2022.100920 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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