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

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. [Display omitted] •CD93 is a marker for leukemia stem cells (LSCs) in CML•The intracellular domain of CD93 promotes stemness and self-renewal of CML LSCs•The anti-emetic drug metoclopramide blocks CD93 signaling in LSCs CD93 is a marker for LSCs in CML, but its broad expression on normal tissue hinders the development of CD93-targeting therapies. Riether et al. show that signaling via the intracellular domain of CD93 selectively promotes self-renewal of LSCs and that this process can be inhibited with the anti-emetic drug metoclopramide.