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

<h4>Background</h4>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 invest...

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Autores principales: Mahban Irandoust, Julian Alvarez Zarate, Isabelle Hubeek, Ellen M van Beek, Karin Schornagel, Aart J F Broekhuizen, Mercan Akyuz, Arjan A van de Loosdrecht, Ruud Delwel, Peter J Valk, Edwin Sonneveld, Pamela Kearns, Ursula Creutzig, Dirk Reinhardt, Eveline S J M de Bont, Eva A Coenen, Marry M van den Heuvel-Eibrink, C Michel Zwaan, Gertjan J L Kaspers, Jacqueline Cloos, Timo K van den Berg
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Publicado: Public Library of Science (PLoS) 2013
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spelling oai:doaj.org-article:4130b2e000fb4e6db767bbaff246bd5c2021-11-18T08:02:20ZEngagement of SIRPα inhibits growth and induces programmed cell death in acute myeloid leukemia cells.1932-620310.1371/journal.pone.0052143https://doaj.org/article/4130b2e000fb4e6db767bbaff246bd5c2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23320069/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Design and methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>Our data indicate that triggering of SIRPα has antileukemic effect and may function as a potential therapeutic target in AML.Mahban IrandoustJulian Alvarez ZarateIsabelle HubeekEllen M van BeekKarin SchornagelAart J F BroekhuizenMercan AkyuzArjan A van de LoosdrechtRuud DelwelPeter J ValkEdwin SonneveldPamela KearnsUrsula CreutzigDirk ReinhardtEveline S J M de BontEva A CoenenMarry M van den Heuvel-EibrinkC Michel ZwaanGertjan J L KaspersJacqueline CloosTimo K van den BergPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 1, p e52143 (2013)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Mahban Irandoust
Julian Alvarez Zarate
Isabelle Hubeek
Ellen M van Beek
Karin Schornagel
Aart J F Broekhuizen
Mercan Akyuz
Arjan A van de Loosdrecht
Ruud Delwel
Peter J Valk
Edwin Sonneveld
Pamela Kearns
Ursula Creutzig
Dirk Reinhardt
Eveline S J M de Bont
Eva A Coenen
Marry M van den Heuvel-Eibrink
C Michel Zwaan
Gertjan J L Kaspers
Jacqueline Cloos
Timo K van den Berg
Engagement of SIRPα inhibits growth and induces programmed cell death in acute myeloid leukemia cells.
description <h4>Background</h4>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.<h4>Design and methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>Our data indicate that triggering of SIRPα has antileukemic effect and may function as a potential therapeutic target in AML.
format article
author Mahban Irandoust
Julian Alvarez Zarate
Isabelle Hubeek
Ellen M van Beek
Karin Schornagel
Aart J F Broekhuizen
Mercan Akyuz
Arjan A van de Loosdrecht
Ruud Delwel
Peter J Valk
Edwin Sonneveld
Pamela Kearns
Ursula Creutzig
Dirk Reinhardt
Eveline S J M de Bont
Eva A Coenen
Marry M van den Heuvel-Eibrink
C Michel Zwaan
Gertjan J L Kaspers
Jacqueline Cloos
Timo K van den Berg
author_facet Mahban Irandoust
Julian Alvarez Zarate
Isabelle Hubeek
Ellen M van Beek
Karin Schornagel
Aart J F Broekhuizen
Mercan Akyuz
Arjan A van de Loosdrecht
Ruud Delwel
Peter J Valk
Edwin Sonneveld
Pamela Kearns
Ursula Creutzig
Dirk Reinhardt
Eveline S J M de Bont
Eva A Coenen
Marry M van den Heuvel-Eibrink
C Michel Zwaan
Gertjan J L Kaspers
Jacqueline Cloos
Timo K van den Berg
author_sort Mahban Irandoust
title Engagement of SIRPα inhibits growth and induces programmed cell death in acute myeloid leukemia cells.
title_short Engagement of SIRPα inhibits growth and induces programmed cell death in acute myeloid leukemia cells.
title_full Engagement of SIRPα inhibits growth and induces programmed cell death in acute myeloid leukemia cells.
title_fullStr Engagement of SIRPα inhibits growth and induces programmed cell death in acute myeloid leukemia cells.
title_full_unstemmed Engagement of SIRPα inhibits growth and induces programmed cell death in acute myeloid leukemia cells.
title_sort engagement of sirpα inhibits growth and induces programmed cell death in acute myeloid leukemia cells.
publisher Public Library of Science (PLoS)
publishDate 2013
url https://doaj.org/article/4130b2e000fb4e6db767bbaff246bd5c
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