2. Academic Validation
  3. Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation

Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation

  • Nature. 2025 Jun;642(8067):508-518. doi: 10.1038/s41586-025-08915-1.
Amir Hosseini # 1,  Abhinav Dhall # 2,  Nemo Ikonen 3,  Natalia Sikora 1,  Sylvain Nguyen 1,  Yuqi Shen 4,  Maria Luisa Jurgensen Amaral 5,  Alan Jiao 1,  Felice Wallner 1,  Philipp Sergeev 3,  Yuhua Lim 1,  Yuanqin Yang 1,  Binje Vick 6 7,  Kimihito Cojin Kawabata 8,  Ari Melnick 8,  Paresh Vyas 4 9,  Bing Ren 5,  Irmela Jeremias 6 7 10,  Bethan Psaila 1 4 9,  Caroline A Heckman 11,  M Andrés Blanco 12,  Yang Shi 13 14
Affiliations

Affiliations

  • 1 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 2 Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 3 Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland.
  • 4 Medical Research Council Weatherall Institute of Molecular Medicine (MRC WIMM), University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.
  • 5 Cell and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • 6 Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany.
  • 7 German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and University Hospital LMU Munich, Munich, Germany.
  • 8 Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA.
  • 9 Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
  • 10 Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
  • 11 Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland. caroline.heckman@helsinki.fi.
  • 12 Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. ablanco@vet.upenn.edu.
  • 13 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. yang.shi@ludwig.ox.ac.uk.
  • 14 Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. yang.shi@ludwig.ox.ac.uk.
  • # Contributed equally.
PMID: 40240608 DOI: 10.1038/s41586-025-08915-1
Abstract

Impaired differentiation is a hallmark of myeloid malignancies1,2. Therapies that enable cells to circumvent the differentiation block, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), are by and large curative in acute promyelocytic leukaemia3, but whether 'differentiation therapy' is a generalizable therapeutic approach for acute myeloid leukaemia (AML) and beyond remains incompletely understood. Here we demonstrate that simultaneous inhibition of the Histone Demethylase LSD1 (LSD1i) and the Wnt pathway antagonist GSK3 kinase4 (GSK3i) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumour burden and significantly extending survival in a patient-derived xenograft mouse model. Mechanistically, this combination promotes differentiation by activating genes in the type I interferon pathway via inducing expression of transcription factors such as IRF7 (LSD1i) and the co-activator β-catenin (GSK3i), and their selective co-occupancy at targets such as STAT1, which is necessary for combination-induced differentiation. Combination treatment also suppresses the canonical, pro-oncogenic Wnt pathway and cell cycle genes. Analysis of datasets from patients with AML suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, this combination strategy rewires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and WNT-driven cancers beyond AML.

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