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Peer-reviewedCC BY 4.0Leukemia

A novel role for transcription factor NFE2 in redox regulation and chemotherapy resistance in acute myeloid leukemia

  • Anne Marie Staehle1
  • Florian Perner2
  • Hans Felix Staehle1
  • Katharina Gellrich1
  • Fiona Preiß1
  • Annika Grafemeyer1
  • Jana Schulze1,3
  • Jean-Luca Funk1
  • Albert Gründer1
  • Julia Berner4,5
  • Sander Bekeschus4,5
  • Christoph Koellerer1
1 more authors
  • Heike L. Pahl1
5 affiliations
  1. 1Department of Hematology/Oncology, Medical Center - University of Freiburg, 79106 Freiburg, Germany
  2. 2Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
  3. 3Faculty of Biology - University of Freiburg, 79106 Freiburg, Germany
  4. 4Leibniz Institute for Plasma Science and Technology (INP), ZIK Plasmatis, Greifswald, Germany
  5. 5Rostock University Medical Center, Clinic and Policlinic for Dermatology, Venerology and Allergology, Rostock, Germany
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Abstract

Elevated activity of transcription factor NFE2 is sufficient to cause leukemic transformation in absence of a classical leukemic driver. However, the molecular mechanism promoting NFE2-driven leukemogenesis is not known. Here we report a previously unrecognized role for NFE2 as a key regulator of the oxidative stress response in leukemic cells. Through a comprehensive analysis of NFE2 genomic occupancy and its effect on chromatin accessibility and transcription, we demonstrate that NFE2 regulates glutathione homeostasis as well as the expression of central detoxifying enzymes. NFE2 constituted one of the highest scoring gene dependencies in MLL-AF9-transformed primary leukemic cells under redox stress, substantially more significant than the universally recognized redox regulator NRF2. Consequently, NFE2 knockdown sensitized leukemic cells to GSH depletion, ferroptosis induction, as well as to cytarabine treatment. Deriving an NFE2 RedOx score, we demonstrate that increased NFE2 activity constitutes an independent predictor of inferior outcome in AML patients at diagnosis.

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Cite

BibTeXRIS
BibTeX
@article{staehle2026novel,
  title = {{A novel role for transcription factor NFE2 in redox regulation and chemotherapy resistance in acute myeloid leukemia}},
  author = {Anne Marie Staehle and Florian Perner and Hans Felix Staehle and Katharina Gellrich and Fiona Preiß and Annika Grafemeyer and Jana Schulze and Jean-Luca Funk and Albert Gründer and Julia Berner and Sander Bekeschus and Christoph Koellerer and Heike L. Pahl},
  journal = {Leukemia},
  year = {2026},
  month = aug,
  doi = {10.1038/s41375-026-03095-x},
  url = {https://doi.org/10.1038/s41375-026-03095-x},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A novel role for transcription factor NFE2 in redox regulation and chemotherapy resistance in acute myeloid leukemia
AU  - Anne Marie Staehle
AU  - Florian Perner
AU  - Hans Felix Staehle
AU  - Katharina Gellrich
AU  - Fiona Preiß
AU  - Annika Grafemeyer
AU  - Jana Schulze
AU  - Jean-Luca Funk
AU  - Albert Gründer
AU  - Julia Berner
AU  - Sander Bekeschus
AU  - Christoph Koellerer
AU  - Heike L. Pahl
PY  - 2026
DA  - 2026/08/19
JO  - Leukemia
DO  - 10.1038/s41375-026-03095-x
UR  - https://doi.org/10.1038/s41375-026-03095-x
AB  - Elevated activity of transcription factor NFE2 is sufficient to cause leukemic transformation in absence of a classical leukemic driver. However, the molecular mechanism promoting NFE2-driven leukemogenesis is not known. Here we report a previously unrecognized role for NFE2 as a key regulator of the oxidative stress response in leukemic cells. Through a comprehensive analysis of NFE2 genomic occupancy and its effect on chromatin accessibility and transcription, we demonstrate that NFE2 regulates glutathione homeostasis as well as the expression of central detoxifying enzymes. NFE2 constituted one of the highest scoring gene dependencies in MLL-AF9-transformed primary leukemic cells under redox stress, substantially more significant than the universally recognized redox regulator NRF2. Consequently, NFE2 knockdown sensitized leukemic cells to GSH depletion, ferroptosis induction, as well as to cytarabine treatment. Deriving an NFE2 RedOx score, we demonstrate that increased NFE2 activity constitutes an independent predictor of inferior outcome in AML patients at diagnosis.
SN  - 0887-6924
SN  - 1476-5551
ER  -