TY - JOUR
T1 - Engagement of SIRPα Inhibits Growth and Induces Programmed Cell Death in Acute Myeloid Leukemia Cells
AU - Irandoust, Mahban
AU - Alvarez Zarate, Julian
AU - Hubeek, Isabelle
AU - van Beek, Ellen M.
AU - Schornagel, Karin
AU - Broekhuizen, Aart J.F.
AU - Akyuz, Mercan
AU - van de Loosdrecht, Arjan A.
AU - Delwel, Ruud
AU - Valk, Peter J.
AU - Sonneveld, Edwin
AU - Kearns, Pamela
AU - Creutzig, Ursula
AU - Reinhardt, Dirk
AU - de Bont, Eveline S.J.M.
AU - Coenen, Eva A.
AU - van den Heuvel-Eibrink, Marry M.
AU - Zwaan, C. Michel
AU - Kaspers, Gertjan J.L.
AU - Cloos, Jacqueline
AU - van den Berg, Timo K.
PY - 2013/1/8
Y1 - 2013/1/8
N2 - 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 (SIRPα) on macrophages. Although AML cells express SIRPα, its function has not been investigated in these cells. In this study we aimed to determine the role of the SIRPα in acute myeloid leukemia. Design and Methods: We analyzed the expression of SIRPα, both on mRNA and protein level in AML patients and we further investigated whether the expression of SIRPα on two low SIRPα expressing AML cell lines could be upregulated upon differentiation of the cells. We determined the effect of chimeric SIRPα 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 SIRPα 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 SIRPα expression had a poor prognosis. Our results also showed that SIRPα is upregulated upon differentiation of NB4 and Kasumi cells. In addition, triggering of SIRPα with an agonistic antibody in the cells stably expressing chimeric SIRPα, led to inhibition of growth and induction of programmed cell death. Finally, the SIRPα-derived signaling synergized with the activity of established antileukemic drugs. Conclusions: Our data indicate that triggering of SIRPα has antileukemic effect and may function as a potential therapeutic target in AML.
AB - 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 (SIRPα) on macrophages. Although AML cells express SIRPα, its function has not been investigated in these cells. In this study we aimed to determine the role of the SIRPα in acute myeloid leukemia. Design and Methods: We analyzed the expression of SIRPα, both on mRNA and protein level in AML patients and we further investigated whether the expression of SIRPα on two low SIRPα expressing AML cell lines could be upregulated upon differentiation of the cells. We determined the effect of chimeric SIRPα 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 SIRPα 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 SIRPα expression had a poor prognosis. Our results also showed that SIRPα is upregulated upon differentiation of NB4 and Kasumi cells. In addition, triggering of SIRPα with an agonistic antibody in the cells stably expressing chimeric SIRPα, led to inhibition of growth and induction of programmed cell death. Finally, the SIRPα-derived signaling synergized with the activity of established antileukemic drugs. Conclusions: Our data indicate that triggering of SIRPα has antileukemic effect and may function as a potential therapeutic target in AML.
UR - http://www.scopus.com/inward/record.url?scp=84872193254&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0052143
DO - 10.1371/journal.pone.0052143
M3 - Article
C2 - 23320069
AN - SCOPUS:84872193254
SN - 1932-6203
VL - 8
JO - PLoS ONE
JF - PLoS ONE
IS - 1
M1 - e52143
ER -