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Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation

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Rombaut, David | Lefèvre, Carine | Rached, Tony | Bondu, Sabrina | Letessier, Anne | Mangione, Raphael | Farhat, Batoul | Lesieur-Pasquier, Auriane | Castillo-Guzman, Daisy | Boussaid, Ismael | Friedrich, Chloé | Tourville, Aurore | de Carvalho, Magali | Levavasseur, Françoise | Leduc, Marjorie | Le Gall, Morgane | Battault, Sarah | Temple, Marie | Houy, Alexandre | Bouscary, Didier | Willems, Lise | Park, Sophie | Raynaud, Sophie | Cluzeau, Thomas | Clappier, Emmanuelle | Fenaux, Pierre | Adès, Lionel | Margueron, Raphael | Wassef, Michel | Alsafadi, Samar | Chapuis, Nicolas | Kosmider, Olivier | Solary, Eric | Constantinou, Angelos | Stern, Marc-Henri | Droin, Nathalie | Palancade, Benoit | Miotto, Benoit | Chédin, Frédéric | Fontenay, Michaela

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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