Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth

Kellaway, Sophie G.; Potluri, Sandeep; Keane, Peter; Blair, Helen J.; Ames, Luke; Worker, Alice; Chin, Paulynn S.; Ptasinska, Anetta; Derevyanko, Polina K.; Adamo, Assunta; Coleman, Daniel J. L.; Khan, Naeem; Assi, Salam A.; Krippner-Heidenreich, Anja; Raghavan, Manoj; Cockerill, Peter N.; Heidenreich, Olaf; Bonifer, Constanze

Abstract

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.

Citation

Kellaway, S. G., Potluri, S., Keane, P., Blair, H. J., Ames, L., Worker, A., Chin, P. S., Ptasinska, A., Derevyanko, P. K., Adamo, A., Coleman, D. J. L., Khan, N., Assi, S. A., Krippner-Heidenreich, A., Raghavan, M., Cockerill, P. N., Heidenreich, O., & Bonifer, C. (2024). Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth. Nature Communications, 15(1), Article 1359. https://doi.org/10.1038/s41467-024-45691-4

• Journal Article Type: Article
• Acceptance Date: Jan 31, 2024
• Online Publication Date: Feb 14, 2024
• Publication Date: 2024
• Deposit Date: Feb 28, 2024
• Publicly Available Date: Feb 29, 2024
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 1
• Article Number: 1359
• DOI: https://doi.org/10.1038/s41467-024-45691-4
• Keywords: General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry; Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/31603025
• Publisher URL: https://www.nature.com/articles/s41467-024-45691-4
• Additional Information: Received: 2 May 2023; Accepted: 31 January 2024; First Online: 14 February 2024; : The authors declare no competing interests.