R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription-Replication Conflicts.

IF 12.5 1区 医学 Q1 ONCOLOGY Cancer research Pub Date : 2024-02-15 DOI:10.1158/0008-5472.CAN-23-3239
Zhiyan Silvia Liu, Sayantani Sinha, Maxwell Bannister, Axia Song, Erica Arriaga-Gomez, Alexander J McKeeken, Elizabeth A Bonner, Benjamin K Hanson, Martina Sarchi, Kouhei Takashima, Dawei Zong, Victor M Corral, Evan Nguyen, Jennifer Yoo, Wannasiri Chiraphapphaiboon, Cassandra Leibson, Matthew C McMahon, Sumit Rai, Elizabeth M Swisher, Zohar Sachs, Srinivas Chatla, Derek L Stirewalt, H Joachim Deeg, Tomasz Skorski, Eirini P Papapetrou, Matthew J Walter, Timothy A Graubert, Sergei Doulatov, Stanley C Lee, Hai Dang Nguyen
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Abstract

RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi), despite being proficient in homologous recombination repair. Instead, SF-mutant leukemias exhibited R-loop accumulation that elicited an R-loop-associated PARP1 response, rendering cells dependent on PARP1 activity for survival. Consequently, PARPi induced DNA damage and cell death in SF-mutant leukemias in an R-loop-dependent manner. PARPi further increased aberrant R-loop levels, causing higher transcription-replication collisions and triggering ATR activation in SF-mutant leukemias. Ultimately, PARPi-induced DNA damage and cell death in SF-mutant leukemias could be enhanced by ATR inhibition. Finally, the level of PARP1 activity at R-loops correlated with PARPi sensitivity, suggesting that R-loop-associated PARP1 activity could be predictive of PARPi sensitivity in patients harboring SF gene mutations. This study highlights the potential of targeting different R-loop response pathways caused by spliceosome gene mutations as a therapeutic strategy for treating cancer.

Significance: Spliceosome-mutant leukemias accumulate R-loops and require PARP1 to resolve transcription-replication conflicts and genomic instability, providing rationale to repurpose FDA-approved PARP inhibitors for patients carrying spliceosome gene mutations.

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剪接体突变型白血病中的r环积累通过触发转录-复制冲突赋予PARP1抑制的敏感性。
RNA剪接因子(SF)基因突变常见于髓系恶性肿瘤患者。本研究表明,尽管SRSF2-和u2af1突变型白血病精通同源重组修复,但它们对PARP抑制剂(PARPi)优先敏感。相反,sf突变白血病表现出r环积累,引发r环相关的PARP1反应,使细胞依赖PARP1活性生存。因此,PARPi在sf突变白血病中以r环依赖的方式诱导DNA损伤和细胞死亡。PARPi进一步增加了异常的r环水平,在sf突变白血病中引起更高的转录-复制碰撞并触发ATR激活。最终,parpi诱导的sf突变白血病的DNA损伤和细胞死亡可以通过ATR抑制而增强。最后,R环上PARP1活性水平与PARPi敏感性相关,表明R环相关PARP1活性可以预测SF基因突变患者PARPi敏感性。这项研究强调了靶向剪接体基因突变引起的不同r环反应途径作为治疗癌症的治疗策略的潜力。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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