Table S8 from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts
posted on 2024-02-15, 08:40authored byZhiyan 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
Alternative splicing analysis of K562 SRSF2-WT and SRSF2-P95H cells
Funding
University of Minnesota (UMN)
National Center for Advancing Translational Sciences (NCATS)
United States Department of Health and Human Services
Vera and Joseph Dresner Foundation (Dresner Foundation)
Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)
Foundation for Barnes-Jewish Hospital (FBJH)
NHLBI Division of Intramural Research (DIR)
History
ARTICLE 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.
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.