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December 8, 2025BloodOpen Access

Replication fork remodeling is a therapeutic vulnerability in acute myeloid leukemia

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Authors

TFTsz Kan FungKing's College LondonTGTristan GasparettoUniversity of ZurichCSChi Wai Eric SoLondon Cancer

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Implication

Findings reveal that DNA damage response and fork plasticity are potential therapeutic targets in AML, suggesting new treatment strategies.

Key Points

  • The study aims to explore how DNA replication dynamics and plasticity contribute to the therapeutic response in AML.
  • Investigated DNA replication dynamics in human and mouse AML models expressing various oncofusion proteins.
  • Utilized single-cell and single-molecule assays, including comet assays, to analyze replication-associated DNA damage.
  • Assessed effects of PARP inhibitors and standard chemotherapeutics on AML cell survival and fork plasticity.
  • Human and mouse AML models showed fast replication fork progression compared to HSPCs.
  • PARPi-sensitive AML lines responded rapidly to PARP inhibitors, leading to fork breakage and DNA damage.
  • Inactivation of RECQ1 helicase suppressed fork progression phenotypes, linking it to PARPi response.

Cite This Study

Fung et al. (2025) studied this question.

synapsesocial.com/papers/693624d74fa91c937236d10bhttps://doi.org/10.1182/blood-2025-5016
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Also Consider

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

  1. 1DOT1L/menin inhibitors target replication fork plasticity and create novel vulnerability to PARP inhibitor in MLL-rearranged AML2025
  2. 2Age-associated non-mutational resistance in acute myeloid leukemia is driven by DNA damage-induced transcriptional heterogeneity2025
  3. 3Targeting DNA repair vulnerabilities to eradicate TP53 mutated AML.2025
  4. 4Targeting a CDH1–TK1–dependent DNA Synthesis Pathway Overcomes Chemoresistance in Acute Myeloid Leukemia2026
  5. 5Abstract LT07: EPIGENETIC VULNERABILITIES DRIVE SURVIVAL OF DRUG-TOLERANT PERSISTERS AND REVEAL THERAPEUTIC OPPORTUNITIES IN AML2026