Replication stress signaling is a therapeutic target in myelodysplastic syndromes with splicing factor mutations
| Autor: | Patrick Wuchter, Arwin Mehralivand, Daniel Nowak, Qingyu Xu, Franziska Hofmann, Georgia Metzgeroth, Eva Altrock, Nanni Schmitt, Verena Nowak, Antje Knaflic, Justine Danner, Vladimir Riabov, Julia Obländer, Johanna Flach, Iris Palme, Wolf-Karsten Hofmann, Ahmed Jawhar, Florian Nolte, Johann-Christoph Jann, Alexander Streuer |
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| Rok vydání: | 2020 |
| Předmět: |
Mutation
Serine-Arginine Splicing Factors DNA damage Somatic cell RNA Splicing Mutant Hematology Biology Cell cycle medicine.disease_cause Phosphoproteins Splicing Factor U2AF Article 03 medical and health sciences Splicing factor 0302 clinical medicine Myelodysplastic Syndromes RNA splicing Cancer research medicine Humans RNA Splicing Factors Gene 030215 immunology |
| Zdroj: | Haematologica |
| ISSN: | 1592-8721 |
| Popis: | Somatic mutations in genes coding for splicing factors, e.g., SF3B1, U2AF1, SRSF2, and others are found in approximately 50% of patients with myelodysplastic syndromes (MDS). These mutations have been predicted to frequently occur early in the mutational hierarchy of the disease, therefore, making them particularly attractive potential therapeutic targets. Recent studies in cell lines engineered to carry splicing factor mutations have revealed a strong association with elevated levels of DNA:RNA intermediates (R-loops) and a dependency on proper ATR function. However, data confirming this hypothesis in a representative cohort of primary MDS patient samples have so far been missing. Using CD34+ cells isolated from MDS patients with and without splicing factor mutations as well as healthy controls we show that splicing factor mutation- associated R-loops lead to elevated levels of replication stress and ATR pathway activation. Moreover, splicing factor mutated CD34+ cells are more susceptible to pharmacological inhibition of ATR resulting in elevated levels of DNA damage, cell cycle blockade, and cell death. This can be enhanced by combination treatment with the low-dose splicing modulatory compound Pladienolide B. We further confirm the direct association between R-loops and ATR sensitivity and the presence of a splicing factor mutation using lentiviral overexpression of wild-type and mutant SRSF2 P95H in cord blood CD34+ cells. Collectively, our results from n=53 MDS patients identify replication stress and associated ATR signaling to be critical pathophysiological mechanisms in primary MDS CD34+ cells carrying splicing factor mutations, and provide a preclinical rationale for targeting ATR signaling in these patients. |
| Databáze: | OpenAIRE |
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