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1. Table S2 from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts

Author

Liu, Zhiyan Silvia, primary, Sinha, Sayantani, primary, Bannister, Maxwell, primary, Song, Axia, primary, Arriaga-Gomez, Erica, primary, McKeeken, Alexander J., primary, Bonner, Elizabeth A., primary, Hanson, Benjamin K., primary, Sarchi, Martina, primary, Takashima, Kouhei, primary, Zong, Dawei, primary, Corral, Victor M., primary, Nguyen, Evan, primary, Yoo, Jennifer, primary, Chiraphapphaiboon, Wannasiri, primary, Leibson, Cassandra, primary, McMahon, Matthew C., primary, Rai, Sumit, primary, Swisher, Elizabeth M., primary, Sachs, Zohar, primary, Chatla, Srinivas, primary, Stirewalt, Derek L., primary, Deeg, H. Joachim, primary, Skorski, Tomasz, primary, Papapetrou, Eirini P., primary, Walter, Matthew J., primary, Graubert, Timothy A., primary, Doulatov, Sergei, primary, Lee, Stanley C., primary, and Nguyen, Hai Dang, primary

Published
2024
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2. Figure S1-S8 from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts

Author

Liu, Zhiyan Silvia, primary, Sinha, Sayantani, primary, Bannister, Maxwell, primary, Song, Axia, primary, Arriaga-Gomez, Erica, primary, McKeeken, Alexander J., primary, Bonner, Elizabeth A., primary, Hanson, Benjamin K., primary, Sarchi, Martina, primary, Takashima, Kouhei, primary, Zong, Dawei, primary, Corral, Victor M., primary, Nguyen, Evan, primary, Yoo, Jennifer, primary, Chiraphapphaiboon, Wannasiri, primary, Leibson, Cassandra, primary, McMahon, Matthew C., primary, Rai, Sumit, primary, Swisher, Elizabeth M., primary, Sachs, Zohar, primary, Chatla, Srinivas, primary, Stirewalt, Derek L., primary, Deeg, H. Joachim, primary, Skorski, Tomasz, primary, Papapetrou, Eirini P., primary, Walter, Matthew J., primary, Graubert, Timothy A., primary, Doulatov, Sergei, primary, Lee, Stanley C., primary, and Nguyen, Hai Dang, primary

Published
2024
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3. R-loop accumulation in spliceosome mutant leukemias confers sensitivity to PARP1 inhibition by triggering transcription-replication conflicts

Author

Liu, Zhiyan Silvia, primary, Sinha, Sayantani, additional, Bannister, Maxwell, additional, Song, Axia, additional, Arriaga-Gomez, Erica, additional, McKeeken, Alexander J., additional, Bonner, Elizabeth A., additional, Hanson, Benjamin K., additional, Sarchi, Martina, additional, Takashima, Kouhei, additional, Zong, Dawei, additional, Corral, Victor M., additional, Nguyen, Evan, additional, Yoo, Jennifer, additional, Chiraphapphaiboon, Wannasiri, additional, Leibson, Cassandra, additional, McMahon, Matthew C., additional, Rai, Sumit, additional, Swisher, Elizabeth M., additional, Sachs, Zohar, additional, Chatla, Srinivas, additional, Stirewalt, Derek L., additional, Deeg, H. Joachim, additional, Skorski, Tomasz, additional, Papapetrou, Eirini P., additional, Walter, Matthew J., additional, Graubert, Timothy A., additional, Doulatov, Sergei, additional, Lee, Stanley C., additional, and Nguyen, Hai Dang, additional

Published
2023
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4. Abstract 6183: PARP inhibitors preferentially sensitize splicing factor mutant myeloid neoplasms

Author

Nguyen, Dang Hai, primary, Sinha, Sayantani, additional, Liu, Zhiyan Silvia, additional, Bannister, Maxwell Henry, additional, Arriaga-Gomez, Erica, additional, Song, Axia, additional, Zong, Dawei, additional, Sarchi, Martina, additional, Corral, Victor, additional, Chiraphapphaiboon, Wannasiri, additional, Yoo, Jennifer, additional, McMahon, Matthew, additional, Leibson, Cassandra, additional, Stirewalt, Derek L., additional, Deeg, H Joachim, additional, Rai, Sumit, additional, Walter, Matthew, additional, Graubert, Timothy A., additional, Doulatov, Sergei, additional, and Lee, Stanley C., additional

Published
2023
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5. Therapeutic Targeting of Spliceosome Mutant Myeloid Neoplasms Via PARP1 Inhibition

Author

Sinha, Sayantani, primary, Liu, Zhiyan Silvia, additional, Bannister, Maxwell, additional, Arriaga-Gomez, Erica, additional, Song, Axia, additional, Zong, Dawei, additional, Sarchi, Martina, additional, Bonner, Elizabeth, additional, Corral, Victor, additional, Leibson, Cassandra, additional, Chiraphapphaiboon, Wannasiri, additional, Stirewalt, Derek, additional, Deeg, Joachim, additional, Rai, Sumit, additional, Walter, Matthew J, additional, Graubert, Timothy A., additional, Doulatov, Sergei, additional, Nguyen, Dang Hai, additional, and Lee, Stanley Chun-Wei, additional

Published
2022
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8. R-loop accumulation induced by splicing perturbation triggers PARP1/2 response

Author

Zong, Dawei

Abstract

Mutation in genes encoding for U2AF1, SRSF2, and SF3B1 are commonly mutated in myelodysplastic syndromes (MDS) and other hematological malignancies, highlighting a unique genetic vulnerability for targeted therapies. Recent studies showed that perturbing RNA splicing by pharmacological modulators selectively sensitizes RNA splicing mutant cancers in vitro and in vivo models. However, the use of pharmacological modulators in clinical trials did not show improved efficacy in patients carrying RNA splicing factor mutations, pointing to a need for drug combination strategies. We previously reported that RNA splicing perturbation caused by pharmacological splicing modulators trigger aberrant accumulation of R-loops, a three-stranded nucleic acid structure consisting of an RNA:DNA hybrid and a displaced single-stranded DNA and depend on R-loop response signaling for survival. Based on these findings, we hypothesize that targeting different R-loop response pathways enhances cancer cell killing when combined with RNA splicing modulators. Here, we identified that RNA splicing modulator, pladienolide B (Plad-B) elicited a poly ADP-ribosylation (PARP) response in an R-loop dependent manner. PARP inhibitor, olaparib, induced more DNA damage in cells treated Plad-B, suggesting a new therapeutic drug combination that may enhance cell death. Surprisingly, we found that the PARP response in Plad-B treated cells requires both PARP1 and PARP2 function. This is in stark contrast to their known functions in DNA repair where PARP1 plays the dominant role. Taken together, we propose a two-step model where PARP1 initiates and PARP2 amplifies the ADP-ribosylation signaling to prevent R-loop-associated genomic instability. Importantly, our results highlight a new R-loop regulatory signaling mediated by PARP1/2 and a potential of repurposing FDA-approved PARP inhibitors to treat MDS patients harboring splicing factor mutations either as a monotherapy or in combination with RNA splicing modulators.

Published
2022

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

Author

Liu ZS, Sinha S, Bannister M, Song A, Arriaga-Gomez E, McKeeken AJ, Bonner EA, Hanson BK, Sarchi M, Takashima K, Zong D, Corral VM, Nguyen E, Yoo J, Chiraphapphaiboon W, Leibson C, McMahon MC, Rai S, Swisher EM, Sachs Z, Chatla S, Stirewalt DL, Deeg HJ, Skorski T, Papapetrou EP, Walter MJ, Graubert TA, Doulatov S, Lee SC, and Nguyen HD

Subjects
Humans, R-Loop Structures, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, DNA Repair, RNA Splicing Factors genetics, Poly (ADP-Ribose) Polymerase-1 genetics, Spliceosomes genetics, Leukemia drug therapy, Leukemia genetics
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., (©2023 American Association for Cancer Research.)

Published
2024
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