Abstract
Myelodysplastic syndromes (MDS) with mutated SF3B1 gene present features including a favourable outcome distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1 . Molecular bases of these divergences are poorly understood. Here we find that SF3B1 -mutated MDS show reduced R-loop formation predominating in gene bodies associated with intron retention reduction, not found in U2AF1 - or SRSF2 -mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1 -mutated patients, SF3B1 -mutated erythroblasts exhibit augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restores R-loop formation, slows down DNA replication forks and improves SF3B1 -mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress represents a hallmark of SF3B1 -mutated MDS ineffective erythropoiesis, which could be used as a therapeutic target.