title: New cellular markers at diagnosis are associated with isolated central nervous system relapse in paediatric B-cell precursor acute lymphoblastic leukaemia.
abstract: In childhood acute lymphoblastic leukaemia (ALL), central nervous system (CNS) involvement is rare at diagnosis (1-4%), but more frequent at relapse (~30%). Because of the significant late sequelae of CNS treatment, early identification of patients at risk of CNS relapse is crucial. Using microarray-analysis, we discovered multiple differentially expressed genes between B-cell precursor (BCP) ALL cells in bone marrow (BM) and BCP-ALL cells in cerebrospinal fluid (CSF) at the time of isolated CNS relapse. After confirmation by real-time quantitative polymerase chain reaction, selected genes (including SCD and SPP1) were validated at the protein level by flowcytometric analysis of BCP-ALL cells in CSF. Further flowcytometric validation showed that a subpopulation of BCP-ALL cells (>1%) with a 'CNS protein profile' (SCD positivity and increased SPP1 expression) was present in the BM at diagnosis in patients who later developed an isolated CNS relapse, whereas this subpopulation was <1% or absent in all other patients. These data indicate that the presence of a (small) subpopulation of BCP-ALL cells with a 'CNS protein profile' at diagnosis (particularly SCD-positivity) is associated with isolated CNS relapse. Such information can be used to design new diagnostic and treatment strategies that aim at prevention of CNS relapse with reduced toxicity.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Vincent H J
authors.initials: VH
authors.lastname: van der Velden
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Daphne
authors.initials: D
authors.lastname: de Launaij
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Jeltje F
authors.initials: JF
authors.lastname: de Vries
authors.affiliation: Dutch Childhood Oncology Group, The Hague, The Netherlands.
authors.forename: Valerie
authors.initials: V
authors.lastname: de Haas
authors.affiliation: Dutch Childhood Oncology Group, The Hague, The Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Sonneveld
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Jane S A
authors.initials: JS
authors.lastname: Voerman
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: de Bie
authors.affiliation: Women's and Children's Hospital, Adelaide, South Australia, Australia.
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.affiliation: Molecular Oncology, Felsenstein Medical Research Centre, Paediatric Haematology Oncology, Tel Aviv University, Schneider Children's Medical Centre of Israel, Petah Tikva, Israel.
authors.forename: Smadar
authors.initials: S
authors.lastname: Avigad
authors.affiliation: Department of Paediatrics, Division of Haematology-Oncology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.
authors.forename: Allen E J
authors.initials: AE
authors.lastname: Yeoh
authors.affiliation: Department of Bioinformatics, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Sigrid M A
authors.initials: SM
authors.lastname: Swagemakers
authors.affiliation: Department of Paediatric Oncology/Haematology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Eckert
authors.affiliation: Dutch Childhood Oncology Group, The Hague, The Netherlands.|Princess Máxima Centre for Paediatric Oncology, Utrecht, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000134:cerebrospinal fluid*; D002490:Central Nervous System / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D004253:DNA Nucleotidylexotransferase / Q000134:cerebrospinal fluid; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D017254:Leukemic Infiltration / Q000175:diagnosis*; D007958:Leukocyte Count; D008297:Male; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D012008:Recurrence
chemical_list: D014408:Biomarkers, Tumor; D004253:DNA Nucleotidylexotransferase
keywords: SCD; SPP1; acute lymphoblastic leukaemia; central nervous system; prediction of CNS relapse