Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation

• 成果类型: Article
• 署名作者: Hosseini, Amir; Dhall, Abhinav; Ikonen, Nemo; Sikora, Natalia; Nguyen, Sylvain; Shen, Yuqi; Amaral, Maria Luisa Jurgensen; Jiao, Alan; Wallner, Felice; Sergeev, Philipp; Lim, Yuhua; Yang, Yuanqin; Vick, Binje; Kawabata, Kimihito Cojin; Melnick, Ari; Vyas, Paresh; Ren, Bing; Jeremias, Irmela; Psaila, Bethan; Heckman, Caroline A.; Blanco, M. Andres; Shi, Yang
• 署名单位: Ludwig Institute for Cancer Research; University of Oxford; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard Medical School; University of Helsinki; University of Oxford; University of California System; University of California San Diego; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Helmholtz Association; German Cancer Research Center (DKFZ); Cornell University; Weill Cornell Medicine; Oxford University Hospitals NHS Foundation Trust; University of Munich; University of Pennsylvania
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1985
• DOI: 10.1038/s41586-025-08915-1
• 发表日期: 2025-06-12
• 关键词: acute myeloid-leukemia; acute promyelocytic leukemia; set enrichment analysis; stem-cells; beta-catenin; retinoic acid; viral mimicry; demethylase 1; activation; inhibitor

摘要

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 beta-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.