Metoclopramide treatment blocks CD93-signaling-mediated self-renewal of chronic myeloid leukemia stem cells

Carsten Riether; Ramin Radpour; Nils M Kallen; Damian T Bürgin; Chantal Bachmann; Christian M Schürch; Ursina Lüthi; Miroslav Arambasic; Sven Hoppe; Christoph E Albers; Gabriela M Baerlocher; Adrian F Ochsenbein

doi:10.1016/j.celrep.2020.108663

Metoclopramide treatment blocks CD93-signaling-mediated self-renewal of chronic myeloid leukemia stem cells

Cell Rep. 2021 Jan 26;34(4):108663. doi: 10.1016/j.celrep.2020.108663.

Affiliations

¹ 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.
² Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
³ 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.
⁴ Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Wirbelsäulenmedizin Bern, Hirslanden Salem-Spital, Bern, Switzerland; Department of Orthopedic Surgery and Traumatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁶ Department of Orthopedic Surgery and Traumatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁷ 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.
⁸ 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.

PMID: 33503440
DOI: 10.1016/j.celrep.2020.108663

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.

Keywords: CD93; chronic myeloid leukemia; leukemia stem cells; metoclopramide; self-renewal.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dopamine D2 Receptor Antagonists / pharmacology
Dopamine D2 Receptor Antagonists / therapeutic use*
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Metoclopramide / pharmacology
Metoclopramide / therapeutic use*
Mice

Substances

Dopamine D2 Receptor Antagonists
Metoclopramide