ReseaRch highlights

PHAGOCytOSIS Don’t eat the HSCs

In two papers published recently in the interaction with its receptor, multipotent progenitors and showed Cell, Irving Weissman and colleagues signal­regulatory protein­α (SIRPα), that increased CD47 expression in identify an important role for CD47 which is expressed by phagocytes. patients with AML is associated in protecting circulating haemato­ But does differential expression of with poor clinical outcomes. Indeed, poietic stem cells (HSCs) and their CD47 have a role in HSC fate? The HSCs could be separated from leu­ progenitors (HSPCs) from phago­ authors showed that the expression kaemia cells based on CD47 expres­ cytosis. They also show that targeting of CD47 is transiently upregulated sion. Targeting of human CD47 CD47, which is constitutively on HSCs by strong mobilizing or with monoclonal antibodies that upregulated on self­renewing inflammatory stimuli. HSCs from block the CD47–SIRPα interaction leukaemia stem cells (LSCs), with Cd47–/– mice failed to engraft in enhanced macrophage phagocytosis monoclonal antibodies enables wild­type mice owing to phago­ of these cells in vitro. Furthermore, a phagocytosis of human LSCs and cytosis of the cells by macrophages. CD47­specific antibody was shown to provides a rationale for the use of In addition, more Cd47+/– than ameliorate AML in vivo in immuno­ CD47­specific antibodies as a therapy wild­type HSPCs were cleared by compromised xenotransplanted for acute myeloid leukaemia (AML). macrophages when chimeric mice mice by specifically targeting AML The absence of CD47 expression with both types of cell were given LSCs for phagocytosis. However, no on cells results in their phago­ a strong inflammatory stimulus. increase in the phagocytosis of cytosis and therefore CD47 acts Previous data have shown that normal HSCs or HSPCs or toxicity as a ‘don’t eat me’ signal through CD47 expression is upregulated in was detected in wild­type mice. bulk leukaemia cells in several mouse So, these papers show that CD47 models. The authors showed that is transiently upregulated on HSCs upregulation of CD47 expression during mobilization to protect them occurred even in the stem and pro­ from phagocytosis by macrophages genitor cells of these mouse leukae­ and that AML LSCs use this protective mias and also showed an upregulation strategy to evade macrophage killing. of CD47 expression by HSCs and Targeting of CD47 preferentially ena­ HSPCs from patients with AML bles the targeting of AML LSCs for and chronic myeloid leukaemia in phagocytosis and therefore mono­ blast crisis. Overexpression of CD47 clonal antibodies that disrupt the in a human myeloid leukaemia cell line CD47–SIRPα interaction could be an that normally expresses low levels of effective therapy for human AML. CD47 increased the tumorigenicity Olive Leavy of these cells in a dose­dependent

manner by increasing their ability to ORIGINAL RESEARCH PAPERS Jaiswal, S. et al. evade macrophage phagocytosis. CD47 is upregulated on circulating Further analyses, published in hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009) | a second paper, confirmed that Majeti, R. et al. CD47 is an adverse prognostic the expression of CD47 is higher factor and therapeutic antibody target on human acute myeloid leukemia stem cells. on human AML LSCs than on Cell 138, 286–299 (2009) normal bone marrow HSCs and

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