骨髓增生异常综合征和急性髓系白血病患者的剪接因子经常发生突变。最近的研究揭示了剪接因子突变引起的聚合分子缺陷，其中 R 环失调和由此产生的基因组不稳定被认为是疾病进展的促成因素。另一方面，了解突变细胞如何在异常 R 环形成和基因组不稳定的情况下生存对于开发新疗法至关重要。进行免疫沉淀是为了鉴定与 PARP1/聚 ADP 核糖基化相关的 R 环。使用蛋白质印迹、免疫荧光和流式细胞术检测 PARP 抑制剂处理后突变细胞的细胞活力、细胞周期停滞、细胞凋亡和 ATM 激活。生成 Srsf2(P95H) 敲入小鼠造血细胞和 MLL-AF9 转化的白血病模型，以研究 PARP 抑制剂作为血液恶性肿瘤治疗的潜力。SRSF2 中的致病突变激活 PARP 并提高整体多聚R 环失调引起的蛋白质 ADP 核糖基化水平。因此，与野生型细胞相比，突变细胞更容易受到 PARP 抑制剂的影响。值得注意的是，合成致死率在Srsf2（P95H）敲入小鼠造血细胞和MLL-AF9白血病模型中得到了进一步验证。我们的研究结果表明，突变细胞通过PARP激活对抗R环破坏引起的基因组威胁，从而使PARP针对 SRSF2 突变的骨髓癌的一种有前景的治疗策略。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Splicing factors are frequently mutated in patients with myelodysplastic syndromes and acute myeloid leukaemia. Recent studies have revealed convergent molecular defects caused by splicing factor mutations, among which R-loop dysregulation and resultant genome instability are suggested as contributing factors to disease progression. On the other hand, understanding how mutant cells survive upon aberrant R-loop formation and genome instability is essential for developing novel therapeutics.The immunoprecipitation was performed to identify R-loops in association with PARP1/poly-ADP-ribosylation. The western blot, immunofluorescence, and flow cytometry assays were used to test the cell viability, cell cycle arrest, apoptosis, and ATM activation in mutant cells following the treatment of the PARP inhibitor. The Srsf2(P95H) knock-in murine hematopoietic cells and MLL-AF9 transformed leukaemia model were generated to investigate the potential of the PARP inhibitor as a therapy for haematological malignancies.The disease-causing mutations in SRSF2 activate PARP and elevate the overall poly-ADP-ribosylation levels of proteins in response to R-loop dysregulation. In accordance, mutant cells are more vulnerable to the PARP inhibitors in comparison to the wild-type counterpart. Notably, the synthetic lethality was further validated in the Srsf2(P95H) knock-in murine hematopoietic cell and MLL-AF9 leukaemia model.Our findings suggest that mutant cells antagonise the genome threat caused by R-loop disruption by PARP activation, thus making PARP targeting a promising therapeutic strategy for myeloid cancers with mutations in SRSF2.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.