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Salik, B.* ; Yi, H.* ; Hassan, N.* ; Santiappillai, N.* ; Vick, B. ; Connerty, P.* ; Duly, A.* ; Trahair, T.* ; Woo, A.J.* ; Beck, D.* ; Liu, T.* ; Spiekermann, K.* ; Jeremias, I. ; Wang, J.* ; Kavallaris, M.* ; Haber, M.* ; Norris, M.D.* ; Liebermann, D.A.* ; D'Andrea, R.J.* ; Murriel, C.* ; Wang, J.Y.*

Targeting RSPO3-LGR4 signaling for leukemia stem cell eradication in acute myeloid leukemia.

Cancer Cell 38, 263-278.e6 (2020)
Postprint DOI
Open Access Green
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 antiRSPO3 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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Publication type Article: Journal article
Document type Scientific Article
Keywords Acute Myeloid Leukemia ; Aml ; Hoxa9 ; Leukemia Stem Cells ; Lgr4 ; Lsc ; Rspo ; Self-renewal ; Signaling Pathway ; Wnt/β-catenin; Beta-catenin; Hematopoietic Stem; Gene-expression; Self-renewal; Mll; Progenitor; Hoxa9; Cancer; Transformation; Maintenance
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 1535-6108
e-ISSN 1878-3686
Journal Cancer Cell
Quellenangaben Volume: 38, Issue: 2, Pages: 263-278.e6 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
POF-Topic(s) 30204 - Cell Programming and Repair
Research field(s) Stem Cell and Neuroscience
PSP Element(s) G-506600-001
DOI 10.1016/j.ccell.2020.05.014
WOS ID WOS:000559591600013
Scopus ID 85088944709
Scopus ID 85086773966
Erfassungsdatum 2020-07-09
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