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

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 SachsSrinivas 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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)577-597
Number of pages21
JournalCancer Research
Volume84
Issue number4
DOIs
StatePublished - 2024

Bibliographical note

Publisher Copyright:
©2023 American Association for Cancer Research.

Fingerprint

Dive into the research topics of 'R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts'. Together they form a unique fingerprint.

Cite this