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

Deepali Pal*, Helen J. Blair, Jessica Parker, Sean Hockney, Melanie Beckett, Mankaran Singh, Ricky Tirtakusuma, Ryan Nelson, Hesta McNeill, Sharon Hanmy Angel, Aaron Wilson, Salem Nizami, Sirintra Nakjang, Shalini Sankar, Peixun Zhou, Claire Schwab, Paul B. Sinclair, Lisa J. Russell, Jonathan Coxhead, Christina HalseyJames M. Allan, Christine J. Harrison, Anthony Vincent Moorman, Heidenreich Olaf, Josef Vormoor

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Article number100717
Number of pages27
JournalCell Reports Medicine
Volume3
Issue number8
DOIs
Publication statusPublished - 16 Aug 2022

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