HiPSC-derived Bone Marrow Milieu Identifies a Clinically Actionable Driver of Niche-mediated Treatment Resistance in Leukemia

Overview

Journal Cell Rep Med

Publisher Cell Press

Specialties Biology
General Medicine

Date 2022 Aug 17

PMID 35977468

Authors

Deepali Pal

Helen Blair

Jessica Parker

Sean Hockney

Melanie Beckett

Mankaran Singh

Ricky Tirtakusuma

Ryan Nelson

Hesta McNeill

Sharon H Angel

Aaron Wilson

Salem Nizami

Sirintra Nakjang

Peixun Zhou

Claire Schwab

Paul Sinclair

Lisa J Russell

Jonathan Coxhead

Christina Halsey

James M Allan

Christine J Harrison

Anthony V Moorman

Olaf Heidenreich

Josef Vormoor

Affiliations

Soon will be listed here.

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.

Citing Articles

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