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

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Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia.
Cancer Cell ( IF 48.8 ) Pub Date : 2020-06-18 , DOI: 10.1016/j.ccell.2020.05.014
Basit Salik ₁ , Hangyu Yi ₁ , Nunki Hassan ₁ , Nancy Santiappillai ₁ , Binje Vick ₂ , Patrick Connerty ₁ , Alastair Duly ₁ , Toby Trahair ₃ , Andrew J Woo ₄ , Dominik Beck ₅ , Tao Liu ₃ , Karsten Spiekermann ₆ , Irmela Jeremias ₇ , Jianlong Wang ₈ , Maria Kavallaris ₉ , Michelle Haber ₃ , Murray D Norris ₃ , Dan A Liebermann ₁₀ , Richard J D'Andrea ₁₁ , Christopher Murriel ₁₂ , Jenny Y Wang ₁

Affiliation

Cancer and Stem Cell Biology Group, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2052, Australia.
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.
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2052, Australia.
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, WA 6009, Australia.
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.
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.
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.
Department of Medicine, Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
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.
Fels Institute for Cancer Research and Molecular Biology and Department of Medical Genetics & Molecular Biochemistry, School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Acute Leukaemia Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
OncoMed Pharmaceuticals, Inc., Redwood City, CA 94063, USA.

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.

中文翻译：

靶向 RSPO3-LGR4 信号传导在急性髓系白血病中清除白血病干细胞。

在异质白血病干细胞 (LSC) 池中驱动异常自我更新的信号决定了急性髓性白血病 (AML) 的侵袭性。我们报告了典型 WNT 信号通路的正调节剂 RSPO-LGR4 上调关键的自我更新基因，并且对于 AML 子集中的 LSC 自我更新至关重要。RSPO2/3 作为干细胞生长因子来阻断分化并促进原发性 AML 患者原始细胞的增殖。RSPO 受体 LGR4 在表观遗传上被上调，并通过与预后不良的预测因子 HOXA9 合作发挥作用。通过临床级抗 RSPO3 抗体 (OMP-131R10/rosmantuzumab) 阻断 RSPO3-LGR4 相互作用会损害自我更新并诱导 AML 患者来源的异种移植物分化，但不会影响正常的造血干细胞，

更新日期：2020-08-10

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