hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:3 |
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| Enthalten in: |
Cell reports. Medicine - 3(2022), 8 vom: 16. Aug., Seite 100717 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pal, Deepali [VerfasserIn] |
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| Links: |
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| Themen: |
7S5I7G3JQL |
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| Anmerkungen: |
Date Completed 19.08.2022 Date Revised 10.02.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1016/j.xcrm.2022.100717 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM344960889 |
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| 245 | 1 | 0 | |a hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia |
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| 500 | |a Date Revised 10.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
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| 650 | 4 | |a treatment resistance | |
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| 700 | 1 | |a Blair, Helen |e verfasserin |4 aut | |
| 700 | 1 | |a Parker, Jessica |e verfasserin |4 aut | |
| 700 | 1 | |a Hockney, Sean |e verfasserin |4 aut | |
| 700 | 1 | |a Beckett, Melanie |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Mankaran |e verfasserin |4 aut | |
| 700 | 1 | |a Tirtakusuma, Ricky |e verfasserin |4 aut | |
| 700 | 1 | |a Nelson, Ryan |e verfasserin |4 aut | |
| 700 | 1 | |a McNeill, Hesta |e verfasserin |4 aut | |
| 700 | 1 | |a Angel, Sharon H |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Aaron |e verfasserin |4 aut | |
| 700 | 1 | |a Nizami, Salem |e verfasserin |4 aut | |
| 700 | 1 | |a Nakjang, Sirintra |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Peixun |e verfasserin |4 aut | |
| 700 | 1 | |a Schwab, Claire |e verfasserin |4 aut | |
| 700 | 1 | |a Sinclair, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Russell, Lisa J |e verfasserin |4 aut | |
| 700 | 1 | |a Coxhead, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Halsey, Christina |e verfasserin |4 aut | |
| 700 | 1 | |a Allan, James M |e verfasserin |4 aut | |
| 700 | 1 | |a Harrison, Christine J |e verfasserin |4 aut | |
| 700 | 1 | |a Moorman, Anthony V |e verfasserin |4 aut | |
| 700 | 1 | |a Heidenreich, Olaf |e verfasserin |4 aut | |
| 700 | 1 | |a Vormoor, Josef |e verfasserin |4 aut | |
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