Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.
Nat Commun. 2024 Apr 8;15(1):3016. doi: 10.1038/s41467-024-46547-7.
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.
骨髓增生异常综合征（MDS）伴 SF3B1 基因突变的特征包括与 SRSF2 或 U2AF1 基因突变的 MDS 相比，预后良好。这些差异的分子基础尚不清楚。我们发现 SF3B1 突变的 MDS 中基因体中 R 环形成减少，与剪接因子基因 SRSF2 或 U2AF1 突变的 MDS 中观察到的减少内含子保留减少有关。与 SRSF2 或 U2AF1 突变患者的红系细胞相比，SF3B1 突变的红系细胞在分化时表现出增强的 DNA 合成、加速的复制叉和单链 DNA 暴露。重要的是，使用伏立诺他抑制组蛋白去乙酰化酶可恢复 R 环形成，减缓 DNA 复制叉并改善 SF3B1 突变的红系细胞分化。总之，与 DNA 复制应激相关的 R 环丢失是 SF3B1 突变的 MDS 无效造血的标志，可作为治疗靶点。
