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Published on: June 30, 2022
R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering
Zhiyan Silvia Liu1,2, Sayantani Sinha3, Maxwell Bannister2
1Molecular Pharmacology and Therapeutics Graduate Program, Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota.
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.
Insights
Mutations in splicing factor genes lead to R-loop accumulation in leukemias, making them sensitive to PARP inhibitors. Targeting R-loop pathways offers a new therapeutic strategy for these cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Splicing factor (SF) gene mutations are frequent in myeloid malignancies.
- SF mutations can alter cellular responses to DNA damage and therapeutic agents.
Purpose of the Study:
- To investigate the sensitivity of SF-mutant leukemias to PARP inhibitors (PARPi).
- To elucidate the underlying mechanisms of PARPi sensitivity in SF-mutant leukemias, focusing on R-loop accumulation and DNA damage response pathways.
Main Methods:
- Analysis of SRSF2- and U2AF1-mutant leukemia cell lines.
- Assessment of R-loop levels and DNA damage in response to PARPi treatment.
- Investigation of the role of PARP1 and ATR in SF-mutant leukemias.
- Correlation of PARP1 activity at R-loops with PARPi sensitivity.
Main Results:
- SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARPi, despite intact homologous recombination repair.
- SF-mutant leukemias exhibit increased R-loop accumulation, leading to PARP1-dependent DNA damage and cell death upon PARPi treatment.
- PARPi treatment exacerbates R-loop accumulation, causing transcription-replication collisions and ATR activation.
- Combined inhibition of PARPi and ATR enhances DNA damage and cell death in SF-mutant leukemias.
- PARP1 activity at R-loops correlates with PARPi sensitivity.
Conclusions:
- SF-mutant leukemias are uniquely dependent on PARP1 due to R-loop accumulation, making them susceptible to PARPi.
- Targeting R-loop associated pathways, including PARP1 and ATR, represents a promising therapeutic strategy for SF-mutant myeloid malignancies.
- R-loop-associated PARP1 activity may serve as a predictive biomarker for PARPi sensitivity in patients with SF gene mutations.
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