title: Engagement of SIRPα 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 (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.
  
  
  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.
authors: Department of Pediatric Hematology/Oncology, VU University Medical Centre, Amsterdam, The Netherlands.
authors: Mahban
authors: M
authors: Irandoust
authors: Julian
authors: J
authors: Alvarez Zarate
authors: Isabelle
authors: I
authors: Hubeek
authors: Ellen M
authors: EM
authors: van Beek
authors: Karin
authors: K
authors: Schornagel
authors: Aart J F
authors: AJ
authors: Broekhuizen
authors: Mercan
authors: M
authors: Akyuz
authors: Arjan A
authors: AA
authors: van de Loosdrecht
authors: Ruud
authors: R
authors: Delwel
authors: Peter J
authors: PJ
authors: Valk
authors: Edwin
authors: E
authors: Sonneveld
authors: Pamela
authors: P
authors: Kearns
authors: Ursula
authors: U
authors: Creutzig
authors: Dirk
authors: D
authors: Reinhardt
authors: Eveline S J M
authors: ES
authors: de Bont
authors: Eva A
authors: EA
authors: Coenen
authors: Marry M
authors: MM
authors: van den Heuvel-Eibrink
authors: C Michel
authors: CM
authors: Zwaan
authors: Gertjan J L
authors: GJ
authors: Kaspers
authors: Jacqueline
authors: J
authors: Cloos
authors: Timo K
authors: TK
authors: van den Berg
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D015972:Gene Expression Regulation, Neoplastic; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D058990:Molecular Targeted Therapy; D011379:Prognosis; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D011971:Receptors, Immunologic; C501920:SIRPA protein, human