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 (2021). Metoclopramide treatment blocks CD93-signaling-mediated self-renewal of chronic myeloid leukemia stem cells. Cell reports, 34(4), p. 108663. Cell Press 10.1016/j.celrep.2020.108663

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Orthopaedic, Plastic and Hand Surgery (DOPH) > Clinic of Orthopaedic Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Tumor-Immunologie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Med. Onkologie / Hämatologie (Erw.)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Med. Onkologie / Hämatologie (Erw.)

UniBE Contributor:

Riether, Carsten; Radpour, Ramin; Bürgin, Damian Timo; Bachmann, Chantal Lea; Lüthi, Ursina; Arambasic, Miroslav; Hoppe, Sven; Albers, Christoph; Baerlocher, Gabriela Maria and Ochsenbein, Adrian

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2211-1247

Publisher:

Cell Press

Language:

English

Submitter:

Rebeka Gerber

Date Deposited:

10 May 2021 16:26

Last Modified:

16 May 2021 03:04

Publisher DOI:

10.1016/j.celrep.2020.108663

PubMed ID:

33503440

Uncontrolled Keywords:

CD93 chronic myeloid leukemia leukemia stem cells metoclopramide self-renewal

BORIS DOI:

10.48350/156171

URI:

https://boris.unibe.ch/id/eprint/156171

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