1. Academic Validation
  2. PARP inhibition leads to synthetic lethality with key splicing-factor mutations in myelodysplastic syndromes

PARP inhibition leads to synthetic lethality with key splicing-factor mutations in myelodysplastic syndromes

  • Br J Cancer. 2024 May 28. doi: 10.1038/s41416-024-02729-0.
Fangliang Zhang # 1 Jianai Sun # 2 3 Lei Zhang 2 Ruiqi Li 1 Yanzhen Wang 1 Huichao Geng 1 Chao Shen 1 Ling Li 4 Liang Chen 5
Affiliations

Affiliations

  • 1 RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China.
  • 2 Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
  • 3 Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
  • 4 Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA. lingli@coh.org.
  • 5 RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China. liang_chen@whu.edu.cn.
  • # Contributed equally.
Abstract

Background: Splicing factors are frequently mutated in patients with myelodysplastic syndromes and acute myeloid leukaemia. Recent studies have revealed convergent molecular defects caused by splicing factor mutations, among which R-loop dysregulation and resultant genome instability are suggested as contributing factors to disease progression. On the other hand, understanding how mutant cells survive upon aberrant R-loop formation and genome instability is essential for developing novel therapeutics.

Methods: The immunoprecipitation was performed to identify R-loops in association with PARP1/poly-ADP-ribosylation. The western blot, immunofluorescence, and flow cytometry assays were used to test the cell viability, cell cycle arrest, Apoptosis, and ATM activation in mutant cells following the treatment of the PARP Inhibitor. The Srsf2(P95H) knock-in murine hematopoietic cells and MLL-AF9 transformed leukaemia model were generated to investigate the potential of the PARP Inhibitor as a therapy for haematological malignancies.

Results: The disease-causing mutations in SRSF2 activate PARP and elevate the overall poly-ADP-ribosylation levels of proteins in response to R-loop dysregulation. In accordance, mutant cells are more vulnerable to the PARP inhibitors in comparison to the wild-type counterpart. Notably, the synthetic lethality was further validated in the Srsf2(P95H) knock-in murine hematopoietic cell and MLL-AF9 leukaemia model.

Conclusions: Our findings suggest that mutant cells antagonise the genome threat caused by R-loop disruption by PARP activation, thus making PARP targeting a promising therapeutic strategy for myeloid cancers with mutations in SRSF2.

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