@article{69540ec366cc4ef88039fcd2daf246a7,
title = "hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia",
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.",
keywords = "cancer microenvironment, dormancy, treatment resistance, iPSC-niche, drugging cancer niche",
author = "Deepali Pal and Blair, {Helen J.} and Jessica Parker and Sean Hockney and Melanie Beckett and Mankaran Singh and Ricky Tirtakusuma and Ryan Nelson and Hesta McNeill and Angel, {Sharon Hanmy} and Aaron Wilson and Salem Nizami and Sirintra Nakjang and Shalini Sankar and Peixun Zhou and Claire Schwab and Sinclair, {Paul B.} and Russell, {Lisa J.} and Jonathan Coxhead and Christina Halsey and Allan, {James M.} and Harrison, {Christine J.} and Moorman, {Anthony Vincent} and Heidenreich Olaf and Josef Vormoor",
note = "Funding information: This study was funded by NC3Rs grants to D.P.; a CCLG project grant to D.P., J.V., and O.H.; and a Wellcome Trust NUSCU award to D.P. We would like to further thank CRUK for program grant no. C27943/A12788 to J.V. and O.H. and NECCR for funding core infrastructure at Wolfson Childhood Cancer Research Centre, Newcastle University. C.J.H. and A.V.M. were funded by Blood Cancer UK (grant no. 15036). The IVIS Spectrum was funded by grant 087961 from the Wellcome Trust. We thank Dr. Malgorzata Firczuk, Medical University of Warsaw, for the PDX samples. We thank Sophie Boyd, Asmida Isa, and Shalini Shankar for technical assistance. We thank the BSU, Newcastle University, for performing the bioinformatics analysis; and Andrew Filby, Andrew Fuller, and Carly Knill at the Flow Cytometry Core Facility, Newcastle University, for assistance with flow cytometry. The study was also funded by the National Centre for the Replacement Refinement and Reduction of Animals in Research (NC3Rs) (NC/P002412/1 and NC/V001639/1, to D.P.), the Children{\textquoteright}s Cancer and Leukaemia Group (CCLG) (CCLGA 2016 05 BH160568, to D.P., J.V., and O.H.), Wellcome Trust NUSCU award (OSR/0190/DPAL/NUSC [to D.P.]), Cancer Research UK (CRUK) grant no. C27943/A12788 (to J.V. and O.H.), and Blood Cancer UK grant no. 15036 (to C.J.H. and A.V.M.).",
year = "2022",
month = aug,
day = "16",
doi = "10.1101/2021.06.18.448490",
language = "English",
volume = "3",
journal = "Cell Reports Medicine",
issn = "2666-3791",
publisher = "Cell Press",
number = "8",
}
