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Targeting RSPO3-LGR4 signaling for leukemia stem cell eradication in acute myeloid leukemia.
Cancer Cell 38, 263-278.e6 (2020)
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
ISSN (print) / ISBN
1535-6108
e-ISSN
1878-3686
Journal
Cancer Cell
Quellenangaben
Volume: 38,
Issue: 2,
Pages: 263-278.e6
Publisher
Cell Press
Publishing Place
Cambridge, Mass.
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)