Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia
Copyright © 2020 Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:38 |
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| Enthalten in: |
Cancer cell - 38(2020), 2 vom: 10. Aug., Seite 263-278.e6 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Salik, Basit [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.03.2021 Date Revised 09.02.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ccell.2020.05.014 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM31138157X |
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| 245 | 1 | 0 | |a Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia |
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| 500 | |a Date Revised 09.02.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a AML | |
| 650 | 4 | |a HOXA9 | |
| 650 | 4 | |a LGR4 | |
| 650 | 4 | |a LSC | |
| 650 | 4 | |a RSPO | |
| 650 | 4 | |a WNT/β-catenin | |
| 650 | 4 | |a acute myeloid leukemia | |
| 650 | 4 | |a leukemia stem cells | |
| 650 | 4 | |a self-renewal | |
| 650 | 4 | |a signaling pathway | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a LGR4 protein, human |2 NLM | |
| 650 | 7 | |a RSPO3 protein, human |2 NLM | |
| 650 | 7 | |a Receptors, G-Protein-Coupled |2 NLM | |
| 650 | 7 | |a Thrombospondins |2 NLM | |
| 700 | 1 | |a Yi, Hangyu |e verfasserin |4 aut | |
| 700 | 1 | |a Hassan, Nunki |e verfasserin |4 aut | |
| 700 | 1 | |a Santiappillai, Nancy |e verfasserin |4 aut | |
| 700 | 1 | |a Vick, Binje |e verfasserin |4 aut | |
| 700 | 1 | |a Connerty, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Duly, Alastair |e verfasserin |4 aut | |
| 700 | 1 | |a Trahair, Toby |e verfasserin |4 aut | |
| 700 | 1 | |a Woo, Andrew J |e verfasserin |4 aut | |
| 700 | 1 | |a Beck, Dominik |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Spiekermann, Karsten |e verfasserin |4 aut | |
| 700 | 1 | |a Jeremias, Irmela |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jianlong |e verfasserin |4 aut | |
| 700 | 1 | |a Kavallaris, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Haber, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Norris, Murray D |e verfasserin |4 aut | |
| 700 | 1 | |a Liebermann, Dan A |e verfasserin |4 aut | |
| 700 | 1 | |a D'Andrea, Richard J |e verfasserin |4 aut | |
| 700 | 1 | |a Murriel, Christopher |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jenny Y |e verfasserin |4 aut | |
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