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Lookup NU author(s): Sandeep Potluri, Dr Helen BlairORCiD, Polina Derevianko, Dan Coleman, Dr Anja Krippner-Heidenreich, Professor Olaf Heidenreich
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.
Author(s): Kellaway SG, Potluri S, Keane P, Blair HJ, Ames L, Worker A, Chin PS, Ptasinska A, Derevyanko PK, Adamo A, Coleman DJL, Khan N, Assi SA, Krippner-Heidenreich A, Raghavan M, Cockerill PN, Heidenreich O, Bonifer C
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2024
Volume: 15
Online publication date: 14/02/2024
Acceptance date: 31/01/2024
Date deposited: 02/04/2025
ISSN (electronic): 2041-1723
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41467-024-45691-4
DOI: 10.1038/s41467-024-45691-4
Data Access Statement: RNA-seq, scRNA-seq, ATAC-seq, DNaseI-seq and ChIP seq data generated in this study have been deposited in the Gene Expression Omnibus (GEO) under accession code GSE226603. Data from cell growth assays, gate percentages from flow cytometry and qPCR data are provided in the Source Data file. Published processed data was obtained from GSE108316 and the Human Cell Atlas https://explore.data.humancellatlas.org/projects/455b46e6-d8ea-4611-861e-de720a562ada. Published raw data was obtained from GSE108316, GSE211095 and GSE29225. Human genome hg38 was downloaded from Ensembl https://www.ensembl.org/info/data/ftp/index.html Source data are provided with this paper.
PubMed id: 38355578
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