Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia.

Salik, B; Yi, H; Hassan, N; Santiappillai, N; Vick, B; Connerty, P; Duly, A; Trahair, T; Woo, AJ; Beck, D; Liu, T; Spiekermann, K; Jeremias, I; Wang, J; Kavallaris, M; Haber, M; Norris, MD; Liebermann, DA; D'Andrea, RJ; Murriel, C; Wang, JY

Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia.

Salik, B Yi, H Hassan, N Santiappillai, N Vick, B Connerty, P Duly, A Trahair, T Woo, AJ Beck, D Liu, T Spiekermann, K Jeremias, I Wang, J Kavallaris, M Haber, M Norris, MD Liebermann, DA D'Andrea, RJ Murriel, C Wang, JY

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Publisher:: Elsevier BV
Publication Type:: Journal Article
Citation:: Cancer cell, 2020, 38, (2), pp. 263-278
Issue Date:: 2020-08

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Field	Value	Language
dc.contributor.author	Salik, B
dc.contributor.author	Yi, H
dc.contributor.author	Hassan, N
dc.contributor.author	Santiappillai, N
dc.contributor.author	Vick, B
dc.contributor.author	Connerty, P
dc.contributor.author	Duly, A
dc.contributor.author	Trahair, T
dc.contributor.author	Woo, AJ
dc.contributor.author	Beck, D
dc.contributor.author	Liu, T
dc.contributor.author	Spiekermann, K
dc.contributor.author	Jeremias, I
dc.contributor.author	Wang, J
dc.contributor.author	Kavallaris, M
dc.contributor.author	Haber, M
dc.contributor.author	Norris, MD
dc.contributor.author	Liebermann, DA
dc.contributor.author	D'Andrea, RJ
dc.contributor.author	Murriel, C
dc.contributor.author	Wang, JY
dc.date.accessioned	2021-03-08T04:52:47Z
dc.date.available	2020-05-18
dc.date.available	2021-03-08T04:52:47Z
dc.date.issued	2020-08
dc.identifier.citation	Cancer cell, 2020, 38, (2), pp. 263-278
dc.identifier.issn	1535-6108
dc.identifier.issn	1878-3686
dc.identifier.uri	http://hdl.handle.net/10453/146915
dc.description.abstract	Signals driving aberrant self-renewal in the heterogeneous leukemia stem cell (LSC) pool determine aggressiveness of acute myeloid leukemia (AML). We report that a positive modulator of canonical WNT signaling pathway, RSPO-LGR4, upregulates key self-renewal genes and is essential for LSC self-renewal in a subset of AML. RSPO2/3 serve as stem cell growth factors to block differentiation and promote proliferation of primary AML patient blasts. RSPO receptor, LGR4, is epigenetically upregulated and works through cooperation with HOXA9, a poor prognostic predictor. Blocking the RSPO3-LGR4 interaction by clinical-grade anti-RSPO3 antibody (OMP-131R10/rosmantuzumab) impairs self-renewal and induces differentiation in AML patient-derived xenografts but does not affect normal hematopoietic stem cells, providing a therapeutic opportunity for HOXA9-dependent leukemia.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier BV
dc.relation.ispartof	Cancer cell
dc.relation.isbasedon	10.1016/j.ccell.2020.05.014
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1109 Neurosciences, 1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.title	Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia.
dc.type	Journal Article
utslib.citation.volume	38
utslib.location.activity	United States
utslib.for	1109 Neurosciences
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Strength - AAI - Advanced Analytics Institute Research Centre
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Electrical and Data Engineering
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2021-03-08T04:52:43Z
pubs.issue	2
pubs.publication-status	Published
pubs.volume	38
utslib.citation.issue	2

Abstract:

Signals driving aberrant self-renewal in the heterogeneous leukemia stem cell (LSC) pool determine aggressiveness of acute myeloid leukemia (AML). We report that a positive modulator of canonical WNT signaling pathway, RSPO-LGR4, upregulates key self-renewal genes and is essential for LSC self-renewal in a subset of AML. RSPO2/3 serve as stem cell growth factors to block differentiation and promote proliferation of primary AML patient blasts. RSPO receptor, LGR4, is epigenetically upregulated and works through cooperation with HOXA9, a poor prognostic predictor. Blocking the RSPO3-LGR4 interaction by clinical-grade anti-RSPO3 antibody (OMP-131R10/rosmantuzumab) impairs self-renewal and induces differentiation in AML patient-derived xenografts but does not affect normal hematopoietic stem cells, providing a therapeutic opportunity for HOXA9-dependent leukemia.

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http://hdl.handle.net/10453/146915