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

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: jwang@ccia.unsw.edu.au.

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

Free article

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

Basit Salik et al. Cancer Cell. 2020.

Free article

. 2020 Aug 10;38(2):263-278.e6.

doi: 10.1016/j.ccell.2020.05.014. Epub 2020 Jun 18.

Authors

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: jwang@ccia.unsw.edu.au.

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.

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Conflict of interest statement

Declaration of Interests C.M. is an employee of OncoMed Pharmaceuticals and owns stock options in the company. The other authors declare no competing interests.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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Full Text Sources