American Association for Cancer Research
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Table S6 from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts

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posted on 2024-02-15, 08:40 authored by 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

BROCA-GO sequencing analysis

Funding

University of Minnesota (UMN)

National Center for Advancing Translational Sciences (NCATS)

United States Department of Health and Human Services

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Masonic Cancer Center, University of Minnesota (MCC)

Randy Shaver Cancer Research and Community Fund (Randy Shaver Cancer Research & Community Fund)

University of Minnesota Foundation (UMF)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Leukemia and Lymphoma Society (LLS)

American Association for Cancer Research (AACR)

National Heart, Lung, and Blood Institute (NHLBI)

American Society of Hematology (ASH)

Edward P. Evans Foundation

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.

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