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Metoclopramide treatment blocks CD93-signaling-mediated self-renewal of chronic myeloid leukemia stem cells.
Riether, Carsten; Radpour, Ramin; Kallen, Nils M; Bürgin, Damian T; Bachmann, Chantal; Schürch, Christian M; Lüthi, Ursina; Arambasic, Miroslav; Hoppe, Sven; Albers, Christoph E; Baerlocher, Gabriela M; Ochsenbein, Adrian F.
Afiliación
  • Riether C; Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland. Electronic address: carsten.riether@dbmr.unibe.ch.
  • Radpour R; Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
  • Kallen NM; Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
  • Bürgin DT; Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
  • Bachmann C; Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland; Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
  • Schürch CM; Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
  • Lüthi U; Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
  • Arambasic M; Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
  • Hoppe S; Wirbelsäulenmedizin Bern, Hirslanden Salem-Spital, Bern, Switzerland; Department of Orthopedic Surgery and Traumatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Albers CE; Department of Orthopedic Surgery and Traumatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Baerlocher GM; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland; Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • Ochsenbein AF; Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland. Electronic address: adrian.ochsenbein@insel.ch.
Cell Rep ; 34(4): 108663, 2021 01 26.
Article en En | MEDLINE | ID: mdl-33503440
ABSTRACT
Self-renewal is a key characteristic of leukemia stem cells (LSCs) responsible for the development and maintenance of leukemia. In this study, we identify CD93 as an important regulator of self-renewal and proliferation of murine and human LSCs, but not hematopoietic stem cells (HSCs). The intracellular domain of CD93 promotes gene transcription via the transcriptional regulator SCY1-like pseudokinase 1 independently of ligation of the extracellular domain. In a drug library screen, we identify the anti-emetic agent metoclopramide as an efficient blocker of CD93 signaling. Metoclopramide treatment reduces murine and human LSCs in vitro and prolongs survival of chronic myeloid leukemia (CML) mice through downregulation of pathways related to stemness and proliferation in LSCs. Overall, these results identify CD93 signaling as an LSC-specific regulator of self-renewal and proliferation and a targetable pathway to eliminate LSCs in CML.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mielógena Crónica BCR-ABL Positiva / Antagonistas de los Receptores de Dopamina D2 / Metoclopramida Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cell Rep Año: 2021 Tipo del documento: Article
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mielógena Crónica BCR-ABL Positiva / Antagonistas de los Receptores de Dopamina D2 / Metoclopramida Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cell Rep Año: 2021 Tipo del documento: Article