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Lookup NU author(s): Professor Olaf Heidenreich
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© 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. This is an open access article under the CC BY-NC-ND license. http://creativecommons.org/licenses/by-nc-nd/4.0/Chromosomal rearrangements that generate novel fusion genes are a hallmark of acute myeloid leukemia (AML). Depletion experiments in cell line models have suggested that their continued expression is required for maintaining their leukemic phenotype and that fusion genes therefore represent ideal cancer-specific therapeutic targets. However, the extent to which this result holds true for the different stages of hematopoietic development in primary cells and whether therapeutic agents can be efficiently delivered to those cells is still unclear. In this study, we demonstrate that primary AML cells harboring the chromosomal translocation t(8;21) are critically dependent on the corresponding fusion gene, RUNX1::RUNX1T1, to suppress differentiation and maintain stemness. Silencing RUNX1::RUNX1T1 expression using small interfering RNA (siRNA)–loaded lipid nanoparticles induces substantial changes in chromatin accessibility, thereby redirecting the leukemia-associated transcriptional network toward a myeloid differentiation program. Single-cell analyses reveal that this transcriptional reprogramming is associated with the depletion of immature stem and progenitor-like cell populations, accompanied by an expansion of granulocytic and eosinophilic/mast cell–like populations with impaired self-renewal capacity. These findings underscore the essential role of RUNX1::RUNX1T1 in sustaining AML and highlight the therapeutic potential of targeting fusion gene expression in primary AML cells.
Author(s): Derevyanko PK, Swart LE, Mata Casimiro LD, van Oort A, du Plessis M, van den Brink L, Ashtiani M, Zwaan CM, Krippner-Heidenreich A, Bonifer C, Schiffelers R, Vormoor J, Kellaway SG, Heidenreich O
Publication type: Article
Publication status: Published
Journal: Blood
Year: 2025
Volume: 146
Issue: 24
Pages: 2963–2978
Online publication date: 11/12/2025
Acceptance date: 13/08/2025
ISSN (print): 0006-4971
ISSN (electronic): 1528-0020
Publisher: Elsevier B.V.
URL: https://doi.org/10.1182/blood.2025028988
DOI: 10.1182/blood.2025028988
PubMed id: 40991849
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