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Lookup NU author(s): Dr Deepali Pal, Dr Helen Blair, Sean Hockney, Dr Melanie Beckett, Mankaran Singh, Ryan Nelson, Hesta McNeill, Sharon Angel, Aaron Wilson, Salem Nizami, Dr Sirintra Nakjang, Dr Peixun Zhou, Claire Schwab, Dr Paul Sinclair, Dr Lisa Russell, Dr Jonathan Coxhead, Professor James Allan, Professor Christine Harrison FRCPath FMedSci, Professor Anthony MoormanORCiD, Professor Olaf Heidenreich
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 The Author(s)Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (iMSC) and vascular niche-like (iANG) hiPSC-derived cells support ex vivo proliferation of patient-derived leukemia cells, affect dormancy, and mediate treatment resistance. iMSCs protect dormant and cycling blasts against dexamethasone, while iANGs protect only dormant blasts. Leukemia proliferation and protection from dexamethasone-induced apoptosis is dependent on cancer-niche interactions mediated by CDH2. Consequently, we test CDH2 antagonist ADH-1 (previously in Phase I/II trials for solid tumors) in a very aggressive patient-derived xenograft leukemia mouse model. ADH-1 shows high in vivo efficacy; ADH-1/dexamethasone combination is superior to dexamethasone alone, with no ADH-1-conferred additional toxicity. These findings provide a proof-of-concept starting point to develop improved, potentially safer therapeutics targeting niche-mediated cancer dependencies in blood cancers.
Author(s): Pal D, Blair H, Parker J, Hockney S, Beckett M, Singh M, Tirtakusuma R, Nelson R, McNeill H, Angel SH, Wilson A, Nizami S, Nakjang S, Zhou P, Schwab C, Sinclair P, Russell LJ, Coxhead J, Halsey C, Allan JM, Harrison CJ, Moorman AV, Heidenreich O, Vormoor J
Publication type: Article
Publication status: Published
Journal: Cell Reports Medicine
Year: 2022
Volume: 3
Issue: 8
Online publication date: 16/08/2022
Acceptance date: 19/07/2022
Date deposited: 02/09/2022
ISSN (electronic): 2666-3791
Publisher: Cell Press
URL: https://doi.org/10.1016/j.xcrm.2022.100717
DOI: 10.1016/j.xcrm.2022.100717
PubMed id: 35977468
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