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

Basit Salik; Hangyu Yi; Nunki Hassan; Nancy Santiappillai; Binje Vick; Patrick Connerty; Alastair Duly; Toby Trahair; Andrew J Woo; Dominik Beck; Tao Liu; Karsten Spiekermann; Irmela Jeremias; Jianlong Wang; Maria Kavallaris; Michelle Haber; Murray D Norris; Dan A Liebermann; Richard J D'Andrea; Christopher Murriel; Jenny Y Wang

doi:10.1016/j.ccell.2020.05.014

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

Cancer Cell. 2020 Aug 10;38(2):263-278.e6. doi: 10.1016/j.ccell.2020.05.014. Epub 2020 Jun 18.

Authors

Basit Salik¹, Hangyu Yi¹, Nunki Hassan¹, Nancy Santiappillai¹, Binje Vick², Patrick Connerty¹, Alastair Duly¹, Toby Trahair³, Andrew J Woo⁴, Dominik Beck⁵, Tao Liu³, Karsten Spiekermann⁶, Irmela Jeremias⁷, Jianlong Wang⁸, Maria Kavallaris⁹, Michelle Haber³, Murray D Norris³, Dan A Liebermann¹⁰, Richard J D'Andrea¹¹, Christopher Murriel¹², Jenny Y Wang¹³

Affiliations

¹ Cancer and Stem Cell Biology Group, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2052, Australia.
² German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), partner site Munich, Munich, Germany; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
³ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2052, Australia.
⁴ Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, WA 6009, Australia.
⁵ Centre for Health Technologies and the School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia; Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Australia, Sydney, Australia.
⁶ German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), partner site Munich, Munich, Germany; Experimental Leukemia and Lymphoma Research (ELLF) Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany.
⁷ German Cancer Consortium (DKTK), partner site Munich, Munich, Germany; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; Department of Pediatrics, Dr. von Hauner Childrens Hospital, Ludwig Maximilians University, Munich, Germany.
⁸ Department of Medicine, Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁹ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2052, Australia; Australian Centre for NanoMedicine and ARC Centre of Excellence in Convergent Bio-Nano-Science and Technology, University of New South Wales, Sydney, NSW 2052, Australia.
¹⁰ Fels Institute for Cancer Research and Molecular Biology and Department of Medical Genetics & Molecular Biochemistry, School of Medicine, Temple University, Philadelphia, PA 19140, USA.
¹¹ Acute Leukaemia Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
¹² OncoMed Pharmaceuticals, Inc., Redwood City, CA 94063, USA.
¹³ Cancer and Stem Cell Biology Group, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: [email protected].

PMID: 32559496
DOI: 10.1016/j.ccell.2020.05.014

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.

Keywords: AML; HOXA9; LGR4; LSC; RSPO; WNT/β-catenin; acute myeloid leukemia; leukemia stem cells; self-renewal; signaling pathway.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acute Disease
Animals
Antibodies, Monoclonal / pharmacology
Cell Line, Tumor
Gene Expression Profiling / methods
Gene Expression Regulation, Leukemic / drug effects
HL-60 Cells
Humans
K562 Cells
Kaplan-Meier Estimate
Leukemia, Myeloid / drug therapy
Leukemia, Myeloid / genetics*
Leukemia, Myeloid / metabolism
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism*
Receptors, G-Protein-Coupled / genetics*
Receptors, G-Protein-Coupled / immunology
Receptors, G-Protein-Coupled / metabolism
Signal Transduction / drug effects
Signal Transduction / genetics*
THP-1 Cells
Thrombospondins / genetics*
Thrombospondins / immunology
Thrombospondins / metabolism
Xenograft Model Antitumor Assays / methods

Substances

Antibodies, Monoclonal
LGR4 protein, human
RSPO3 protein, human
Receptors, G-Protein-Coupled
Thrombospondins