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Hosseini, A.* ; Dhall, A.* ; Ikonen, N.* ; Sikora, N.* ; Nguyen, S.* ; Shen, Y.* ; Amaral, M.L.J.* ; Jiao, A.L.* ; Wallner, F.* ; Sergeev, P.* ; Lim, Y.H.* ; Yang, Y.* ; Vick, B. ; Kawabata, K.C.* ; Melnick, A.* ; Vyas, P.* ; Ren, B.* ; Jeremias, I. ; Psaila, B.* ; Heckman, C.A.* ; Blanco, M.A.* ; Shi, Y.*

Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation.

Nature, DOI: 10.1038/s41586-025-08915-1 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)