Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation

Impaired differentiation is a hallmark of myeloid malignancies<sup>1,2</sup>. 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 leukaemia<sup>3</sup>, 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 kinase<sup>4</sup> (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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Journal
Nature
Published
2025-04-16
DOI
https://doi.org/10.1038/s41586-025-08915-1
Citations
11
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
19.47
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article

Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation

Abhinav Dhall, Kimihito C. Kawabata, Ari Melnick, Nemo Ikonen et al.
11 citations
Nature
Acute Myeloid Leukemia Research
19.47
article

Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation

Abhinav Dhall, Kimihito C. Kawabata, Ari Melnick, Nemo Ikonen, Amir Hosseini, Philipp Sergeev, Yang Shi, Bethan Psaila, Binje Vick, Irmela Jeremias, Caroline A. Heckman, Andrés Blanco, Y. Lim, Bing Ren, Paresh Vyas, Fredrik K. Wallner, Sylvain Nguyen, Margarida D. Amaral, Alan L. Jiao, Yuanqin Yang, Yuqi Shen, Natalia Sikora
article en
11 citations

Abstract

Impaired differentiation is a hallmark of myeloid malignancies<sup>1,2</sup>. 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 leukaemia<sup>3</sup>, 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 kinase<sup>4</sup> (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.

NatureVol. 642(8067)
Boston Children's Hospital (US), University of Helsinki (FI), Harvard University (US), Cornell University (US), John Radcliffe Hospital (GB), Helmholtz Zentrum München (DE), LMU Klinikum (DE), University of California San Diego (US), University of Oxford (GB), Ludwig Cancer Research (GB), MRC Weatherall Institute of Molecular Medicine (GB), German Center for Infection Research (DE), MRC Human Immunology Unit (GB), Institute for Molecular Medicine Finland (FI), Oxford University Hospitals NHS Trust (GB), Weill Cornell Medicine (US), University of Pennsylvania (US), Ludwig-Maximilians-Universität München (DE)
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Acute Myeloid Leukemia Research
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