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Replication stress signaling is a therapeutic target in myelodysplastic syndromes with splicing factor mutations. | LitMetric

AI Article Synopsis

  • Somatic mutations in splicing factor genes are present in about 50% of Myelodysplastic Syndromes (MDS) patients, making them key targets for therapy.
  • Research shows that these mutations lead to increased DNA:RNA intermediates (R-loops) and reliance on ATR function, contributing to replication stress.
  • The study found that CD34+ cells with splicing factor mutations are more vulnerable to ATR inhibition, resulting in heightened DNA damage and cell death, suggesting that targeting ATR signaling could be an effective treatment strategy in MDS patients.

Article Abstract

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 low-dose splicing modulatory compound Pladienolide B. We further confirm the direct association of R-loops and ATR sensitivity with 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561278PMC
http://dx.doi.org/10.3324/haematol.2020.254193DOI Listing

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