Engagement of SIRP? inhibits growth and induces programmed cell death in acute myeloid leukemia cells.

ABSTRACT: BACKGROUND:Recent studies show the importance of interactions between CD47 expressed on acute myeloid leukemia (AML) cells and the inhibitory immunoreceptor, signal regulatory protein-alpha (SIRP?) on macrophages. Although AML cells express SIRP?, its function has not been investigated in these cells. In this study we aimed to determine the role of the SIRP? in acute myeloid leukemia. DESIGN AND METHODS:We analyzed the expression of SIRP?, both on mRNA and protein level in AML patients and we further investigated whether the expression of SIRP? on two low SIRP? expressing AML cell lines could be upregulated upon differentiation of the cells. We determined the effect of chimeric SIRP? expression on tumor cell growth and programmed cell death by its triggering with an agonistic antibody in these cells. Moreover, we examined the efficacy of agonistic antibody in combination with established antileukemic drugs. RESULTS:By microarray analysis of an extensive cohort of primary AML samples, we demonstrated that SIRP? is differentially expressed in AML subgroups and its expression level is dependent on differentiation stage, with high levels in FAB M4/M5 AML and low levels in FAB M0-M3. Interestingly, AML patients with high SIRP? expression had a poor prognosis. Our results also showed that SIRP? is upregulated upon differentiation of NB4 and Kasumi cells. In addition, triggering of SIRP? with an agonistic antibody in the cells stably expressing chimeric SIRP?, led to inhibition of growth and induction of programmed cell death. Finally, the SIRP?-derived signaling synergized with the activity of established antileukemic drugs. CONCLUSIONS:Our data indicate that triggering of SIRP? has antileukemic effect and may function as a potential therapeutic target in AML.

SUBMITTER: Irandoust M 

PROVIDER: S-EPMC3540026 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature