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

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

doi:10.1016/j.xcrm.2022.100717

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

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. AllanChristine J. Harrison, Anthony V. Moorman, Olaf Heidenreich, Josef Vormoor

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

10 Citaten (Scopus)

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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.

Originele taal-2	Engels
Artikelnummer	100717
Pagina's (van-tot)	100717
Tijdschrift	Cell Reports Medicine
Volume	3
Nummer van het tijdschrift	8
DOI's	https://doi.org/10.1016/j.xcrm.2022.100717
Status	Gepubliceerd - 16 aug. 2022

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10.1016/j.xcrm.2022.100717

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Pal, D., Blair, H., Parker, J., Hockney, S., Beckett, M., Singh, M., Tirtakusuma, R., Nelson, R., McNeill, H., Angel, S. H., Wilson, A., Nizami, S., Nakjang, S., Zhou, P., Schwab, C., Sinclair, P., Russell, L. J., Coxhead, J., Halsey, C., ... Vormoor, J. (2022). hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia. Cell Reports Medicine, 3(8), 100717. Artikel 100717. https://doi.org/10.1016/j.xcrm.2022.100717

@article{1acd06889bba4b3a9732cbeb89e79f75,

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, drugging cancer niche, iPSC-niche, treatment resistance, Bone Marrow/pathology, Neoplasms/pathology, Leukemia/pathology, Humans, Tumor Microenvironment, Drug Resistance, Neoplasm, Animals, Dexamethasone/pharmacology, Mice, Induced Pluripotent Stem Cells",

author = "Deepali Pal and Helen Blair and Jessica Parker and Sean Hockney and Melanie Beckett and Mankaran Singh and Ricky Tirtakusuma and Ryan Nelson and Hesta McNeill and Angel, {Sharon H.} and Aaron Wilson and Salem Nizami and Sirintra Nakjang and Peixun Zhou and Claire Schwab and Paul Sinclair and Russell, {Lisa J.} and Jonathan Coxhead and Christina Halsey and Allan, {James M.} and Harrison, {Christine J.} and Moorman, {Anthony V.} and Olaf Heidenreich and Josef Vormoor",

year = "2022",

month = aug,

day = "16",

doi = "10.1016/j.xcrm.2022.100717",

language = "English",

volume = "3",

pages = "100717",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "8",

}

Pal, D, Blair, H, Parker, J, Hockney, S, Beckett, M, Singh, M, Tirtakusuma, R, Nelson, R, McNeill, H, Angel, SH, Wilson, A, Nizami, S, Nakjang, S, Zhou, P, Schwab, C, Sinclair, P, Russell, LJ, Coxhead, J, Halsey, C, Allan, JM, Harrison, CJ, Moorman, AV, Heidenreich, O & Vormoor, J 2022, 'hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia', Cell Reports Medicine, vol. 3, nr. 8, 100717, blz. 100717. https://doi.org/10.1016/j.xcrm.2022.100717

TY - JOUR

T1 - hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia

AU - Pal, Deepali

AU - Blair, Helen

AU - Parker, Jessica

AU - Hockney, Sean

AU - Beckett, Melanie

AU - Singh, Mankaran

AU - Tirtakusuma, Ricky

AU - Nelson, Ryan

AU - McNeill, Hesta

AU - Angel, Sharon H.

AU - Wilson, Aaron

AU - Nizami, Salem

AU - Nakjang, Sirintra

AU - Zhou, Peixun

AU - Schwab, Claire

AU - Sinclair, Paul

AU - Russell, Lisa J.

AU - Coxhead, Jonathan

AU - Halsey, Christina

AU - Allan, James M.

AU - Harrison, Christine J.

AU - Moorman, Anthony V.

AU - Heidenreich, Olaf

AU - Vormoor, Josef

PY - 2022/8/16

Y1 - 2022/8/16

N2 - 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.

AB - 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.

KW - cancer microenvironment

KW - dormancy

KW - drugging cancer niche

KW - iPSC-niche

KW - treatment resistance

KW - Bone Marrow/pathology

KW - Neoplasms/pathology

KW - Leukemia/pathology

KW - Humans

KW - Tumor Microenvironment

KW - Drug Resistance, Neoplasm

KW - Animals

KW - Dexamethasone/pharmacology

KW - Mice

KW - Induced Pluripotent Stem Cells

UR - http://www.scopus.com/inward/record.url?scp=85135921416&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2022.100717

DO - 10.1016/j.xcrm.2022.100717

M3 - Article

C2 - 35977468

AN - SCOPUS:85135921416

SN - 2666-3791

VL - 3

SP - 100717

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 8

M1 - 100717

ER -

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

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