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

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...

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Bibliographic Details
Published in:Cell reports. Medicine 2022-08, Vol.3 (8), p.100717, Article 100717
Main Authors: Pal, Deepali, Blair, Helen, Parker, Jessica, Hockney, Sean, Beckett, Melanie, Singh, Mankaran, Tirtakusuma, Ricky, Nelson, Ryan, McNeill, Hesta, Angel, Sharon H, Wilson, Aaron, Nizami, Salem, Nakjang, Sirintra, Zhou, Peixun, Schwab, Claire, Sinclair, Paul, Russell, Lisa J, Coxhead, Jonathan, Halsey, Christina, Allan, James M, Harrison, Christine J, Moorman, Anthony V, Heidenreich, Olaf, Vormoor, Josef
Format: Article
Language:English
Subjects:
Animals
Bone Marrow - pathology
Dexamethasone - pharmacology
Drug Resistance, Neoplasm
Humans
Induced Pluripotent Stem Cells
Leukemia - pathology
Mice
Neoplasms - pathology
Tumor Microenvironment
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Summary: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.
ISSN:2666-3791
2666-3791
DOI:10.1016/j.xcrm.2022.100717