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December 8, 2025BloodOpen Access

DOT1L/menin inhibitors target replication fork plasticity and create novel vulnerability to PARP inhibitor in MLL-rearranged AML

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Authors

TFTsz Kan FungKing's College LondonCDCyril DördelmannUniversity of ZurichDPDanyue PengLondon Cancer

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Overview

Inhibition of DOT1L and MENIN alters replication fork dynamics in MLL-rearranged AML, suggesting new treatment strategies with PARP inhibitors.

Key Points

  • This research aims to explore the effects of DOT1L and MENIN inhibitors on replication fork dynamics in MLL-rearranged acute myeloid leukemia.
  • Performed RNA-seq on MLL-AF9 AML cells and MV4;11 cell line with and without DOT1Li or MENINi.
  • Utilized DNA fibre assays to assess replication fork stability and dynamics.
  • Developed an MLL-AF9 leukemia model using mouse HSPCs for functional studies.
  • DOT1Li and MENINi treatment resulted in altered replication fork dynamics.
  • Combination therapy with PARP inhibitors significantly suppressed cell growth in MLLr-AML.
  • In vivo, combination treatments extended disease latency, keeping animals disease-free at the endpoint.

Cite This Study

Fung et al. (2025) studied this question.

synapsesocial.com/papers/69362f4b4fa91c937236d763https://doi.org/10.1182/blood-2025-867
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Also Consider

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

  1. 1Replication fork remodeling is a therapeutic vulnerability in acute myeloid leukemia2025
  2. 2Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia2024 · 21 citations
  3. 3Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia2024 · 48 citations
  4. 4Co-targeting menin and LSD1 dismantles oncogenic programs and restores differentiation in MLL-rearranged AML2025 · 1 citations
  5. 5Synergistic targeting of KMT2A-rearranged AML with combined LSD1 and menin inhibitors2025