Disruption of SIRPα signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts

Theocharides, Alexandre P A; Jin, Liqing; Cheng, Po-Yan; Prasolava, Tatiana K; Malko, Andrei V; Ho, Jenny M; Poeppl, Armando G; van Rooijen, Nico; Minden, Mark D; Danska, Jayne S; Dick, John E; Wang, Jean C Y (2012). Disruption of SIRPα signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts. Journal of experimental medicine, 209(10), pp. 1883-99. New York, N.Y.: Rockefeller University Press 10.1084/jem.20120502

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Although tumor surveillance by T and B lymphocytes is well studied, the role of innate immune cells, in particular macrophages, is less clear. Moreover, the existence of subclonal genetic and functional diversity in some human cancers such as leukemia underscores the importance of defining tumor surveillance mechanisms that effectively target the disease-sustaining cancer stem cells in addition to bulk cells. In this study, we report that leukemia stem cell function in xenotransplant models of acute myeloid leukemia (AML) depends on SIRPα-mediated inhibition of macrophages through engagement with its ligand CD47. We generated mice expressing SIRPα variants with differential ability to bind human CD47 and demonstrated that macrophage-mediated phagocytosis and clearance of AML stem cells depend on absent SIRPα signaling. We obtained independent confirmation of the genetic restriction observed in our mouse models by using SIRPα-Fc fusion protein to disrupt SIRPα-CD47 engagement. Treatment with SIRPα-Fc enhanced phagocytosis of AML cells by both mouse and human macrophages and impaired leukemic engraftment in mice. Importantly, SIRPα-Fc treatment did not significantly enhance phagocytosis of normal hematopoietic targets. These findings support the development of therapeutics that antagonize SIRPα signaling to enhance macrophage-mediated elimination of AML.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory

UniBE Contributor:

Theocharides, Alexandre

ISSN:

0022-1007

Publisher:

Rockefeller University Press

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:28

Last Modified:

17 Mar 2015 21:12

Publisher DOI:

10.1084/jem.20120502

PubMed ID:

22945919

Web of Science ID:

000309219400014

URI:

https://boris.unibe.ch/id/eprint/10382 (FactScience: 216254)

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