Engagement of SIRPα Inhibits Growth and Induces Programmed Cell Death in Acute Myeloid Leukemia Cells

PLoS One

Edwin Sonneveld¹  Pamela Kearns¹  Julian Alvarez Zarate²  Peter J. Valk²  Karin Schornagel²  Jacqueline Cloos³  Gertjan J. L. Kaspers³  C. Michel Zwaan³  Eva A. Coenen⁴  Eveline S. J. M. de Bont⁴  Ruud Delwel⁵  Mahban Irandoust⁵  Timo K. van den Berg⁵  Ellen M. van Beek⁵  Arjan A. van de Loosdrecht⁵  Ursula Creutzig⁶  Aart J. F. Broekhuizen⁷  Isabelle Hubeek⁷  Mercan Akyuz⁷  Dirk Reinhardt⁸  Marry M. van den Heuvel-Eibrink⁹ 

[1] Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;Department of Hematology, VU University Medical Centre, Amsterdam, The Netherlands;Department of Pediatric Hematology/Oncology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands;Department of Pediatric Hematology/Oncology, Medical School Hannover, Hannover, Germany;Department of Pediatric Hematology/Oncology, VU University Medical Centre, Amsterdam, The Netherlands;Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands;Sanquin Research & Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands;School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;University Medical Center Groningen, Groningen, The Netherlands

关键词: Acute myeloid leukemia;    Cell differentiation;    Apoptosis;    Cell death;    Pediatrics;    DNA methylation;    Gene expression;    Protein expression;   

DOI  :  10.1371/journal.pone.0052143

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY