hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia

Pal, D. et al. (2022) hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia. Cell Reports Medicine, 3(8), 100717. (doi: 10.1016/j.xcrm.2022.100717) (PMID:35977468)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Halsey, Professor Chris
Creator Roles:
Halsey, C.Writing – review and editing
Authors: Pal, D., Blair, H., Parker, J., Hockney, S., Beckett, M., Singh, M., Tirtakusuma, R., Nelson, R., McNeill, H., Angel, S. H., Wilson, A., Nizami, S., Nakjang, S., Zhou, P., Schwab, C., Sinclair, P., Russell, L. J., Coxhead, J., Halsey, C., Allan, J. M., Harrison, C. J., Moorman, A. V., Heidenreich, O., and Vormoor, J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Reports Medicine
Publisher:Elsevier (Cell Press)
ISSN:2666-3791
ISSN (Online):2666-3791
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Cell Reports Medicine 3(8): 100717
Publisher Policy:Reproduced under a Creative Commons License

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