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Genome sequencing of primary cells from patients with myelodysplastic syndromes (MDS) led to the identification of recurrent heterozygous mutations in gene encoding components of the spliceosome, the cellular machinery which processes pre-messenger RNA (mRNA) to mature mRNA during gene transcription. Splicing mutations are mutually exclusive with one another and collectively represent the most common mutation class in MDS, occurring in approximately 60 % of patients overall and more than 80 % of those with ring sideroblasts. Evidence from animal models suggests that homozygous splicing mutations are lethal, and that in heterozygously mutated models, any further disruption of splicing triggers apoptosis and cell death. MDS cells with spliceosome mutations are thus uniquely vulnerable to therapies targeting splicing, which may be tolerated by healthy cells. The spliceosome is emerging as a novel therapeutic target in MDS and related myeloid neoplasms, with the first clinical trial of a splicing modulator opening in 2016.

Original publication




Journal article


Curr Hematol Malig Rep

Publication Date





408 - 415


E7107, Myelodysplastic syndromes, SF3B1, Splicing, Targeted therapy, Animals, Epoxy Compounds, Hematologic Neoplasms, Humans, Indoles, Macrolides, Mutation, Myelodysplastic Syndromes, Myeloproliferative Disorders, RNA Splicing, RNA Splicing Factors, Ribonucleoprotein, U2 Small Nuclear, Spliceosomes