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December 8, 2025BloodOpen Access

An actionable DNA repair defect in myeloid malignancies with U2AF1 S34 mutations

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Authors

SAShuhei AsadaYHYuna Hirohashi

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Overview

Experiment demonstrates synthetic lethality in myeloid malignancies including chronic myelomonocytic leukemia, suggesting possible treatment pathways.

Key Points

  • To investigate the actionable DNA repair defect associated with U2AF1 S34 mutations in myeloid malignancies.
  • Analyzed RNA-seq data for U2AF1 S34 mutations in myeloid malignancies.
  • Performed genetic perturbation using CRISPR-Cas9 to identify dependencies in DNA repair pathways.
  • Evaluated sensitivity of U2AF1 S34F mutant cells to inhibitors targeting DNA repair pathways.
  • U2AF1 S34F mutants are functionally MMEJ-deficient and rely on synthetic lethality.
  • Increased sensitivity to CDK12 inhibitor and RBM39 degrader in U2AF1 S34F mutant cells.
  • Mutant cells showed reduced POLQ protein levels, impacting MMEJ activity.

Cite This Study

Asada et al. (2025) studied this question.

synapsesocial.com/papers/69362f5d4fa91c937236dc46https://doi.org/10.1182/blood-2025-215
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Transcriptional and splicing dysregulation by U2AF1 mutations contribute to inflammatory and migratory alterations in MDS2025
  2. 2U2af1S34F and U2af1Q157R myeloid neoplasm-associated hotspot mutations induce distinct hematopoietic phenotypes in mice2026 · 1 citations
  3. 3Comprehensive Analyses of the Effects of the Small-Molecule Inhibitor of the UHM Domain in the Splicing Factor U2AF1 in Leukemia Cells2024 · 4 citations
  4. 4Genomic landscape, clinical correlates and prognostic implications of U2AF1 mutation subtypes in myelodysplastic neoplasms2026
  5. 5Mutant U2AF1-Induced Mis-Splicing of mRNA Translation Genes Confers Resistance to Chemotherapy in Acute Myeloid Leukemia2024 · 17 citations