Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation

Amir Hosseini, Abhinav Dhall, Nemo Ikonen, Natalia Sikora, Sylvain Nguyen, Yuqi Shen, Maria Luisa Jurgensen Amaral, Alan Jiao, Felice Wallner, Philipp Sergeev, Yuhua Lim, Yuanqin Yang, Binje Vick, Kimihito Cojin Kawabata, Ari Melnick, Paresh Vyas, Bing Ren, Irmela Jeremias, Bethan Psaila, Caroline A. Heckman (), M. Andrés Blanco () and Yang Shi ()
Additional contact information
Amir Hosseini: University of Oxford
Abhinav Dhall: Harvard Medical School
Nemo Ikonen: University of Helsinki
Natalia Sikora: University of Oxford
Sylvain Nguyen: University of Oxford
Yuqi Shen: Headington
Maria Luisa Jurgensen Amaral: University of California San Diego
Alan Jiao: University of Oxford
Felice Wallner: University of Oxford
Philipp Sergeev: University of Helsinki
Yuhua Lim: University of Oxford
Yuanqin Yang: University of Oxford
Binje Vick: German Research Center for Environmental Health
Kimihito Cojin Kawabata: Weill Cornell Medicine
Ari Melnick: Weill Cornell Medicine
Paresh Vyas: Headington
Bing Ren: University of California San Diego
Irmela Jeremias: German Research Center for Environmental Health
Bethan Psaila: University of Oxford
Caroline A. Heckman: University of Helsinki
M. Andrés Blanco: University of Pennsylvania
Yang Shi: University of Oxford

Nature, 2025, vol. 642, issue 8067, 508-518

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-08915-1

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