title: EMP1, a novel poor prognostic factor in pediatric leukemia regulates prednisolone resistance, cell proliferation, migration and adhesion.
abstract: Still 20% of pediatric acute lymphoblastic leukemia (ALL) patients relapse on or after current treatment strategies. Treatment failure is associated with resistance to prednisolone. We aimed to find new druggable targets that modulate prednisolone resistance. We generated microarray gene expression profiles of 256 pediatric ALL patient samples and identified a 3.4-fold increase in epithelial membrane protein 1 (EMP1) expression in in vitro prednisolone-resistant compared with -sensitive patients (P=0.003). EMP1 silencing in six precursor-B ALL (BCP-ALL) and T-ALL cell lines induced apoptosis and cell-cycle arrest leading to 84.1±4.5% reduction in survival compared with non-silencing control transduced cells (non-silencing control short hairpin, shNSC) (P=0.014). Moreover, EMP1 silencing sensitized to prednisolone up to 18.8-fold (P<0.001). EMP1 silencing also abrogated migration and adhesion to mesenchymal stromal cells (MSCs) by 78.3±9.0 and 29.3±4.1% compared with shNSC (P<0.05). We discovered that EMP1 contributes to MSC-mediated prednisolone resistance. Pathway analysis indicated that EMP1 signals through the Src kinase family. EMP1-high BCP-ALL patients showed a poorer 5-year event-free survival compared with EMP1-low patients (77±2 vs. 89±2%, P=0.003). Multivariate analysis taking along white blood cell count, age, prednisolone resistance and subtype identified EMP1 as an independent predictor for poor outcome in BCP-ALL (P=0.004, hazard ratio: 2.36 (1.31-4.25). This study provides preclinical evidence that EMP1 is an interesting candidate for drug development to optimize treatment of BCP-ALL.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: I M
authors.initials: IM
authors.lastname: Ariës
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: I S
authors.initials: IS
authors.lastname: Jerchel
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: R E S R
authors.initials: RE
authors.lastname: van den Dungen
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: L C J
authors.initials: LC
authors.lastname: van den Berk
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Boer
authors.affiliation: Clinic of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: Horstmann
authors.affiliation: Clinic of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Escherich
authors.affiliation: 1] Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands [2] Dutch Childhood Oncology Group, The Hague, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.affiliation: 1] Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands [2] Dutch Childhood Oncology Group, The Hague, The Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: den Boer
mesh_terms: D017209:Apoptosis; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D057809:HEK293 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016328:NF-kappa B / Q000502:physiology; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology*; D011239:Prednisolone / Q000494:pharmacology*; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000032:analysis / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D016328:NF-kappa B; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; C097051:epithelial membrane protein-1; D011239:Prednisolone; D019061:src-Family Kinases