title: High interleukin-15 expression characterizes childhood acute lymphoblastic leukemia with involvement of the CNS.
abstract: OBJECTIVE
  Applying current diagnostic methods, overt CNS involvement is a rare event in childhood acute lymphoblastic leukemia (ALL). In contrast, CNS-directed therapy is essential for all patients with ALL because without it, the majority of patients eventually will experience relapse. To approach this discrepancy and to explore potential distinct biologic properties of leukemic cells that migrate into the CNS, we compared gene expression profiles of childhood ALL patients with initial CNS involvement with the profiles of CNS-negative patients.
  
  
  METHODS
  We evaluated leukemic gene expression profiles from the bone marrow of 17 CNS-positive patients and 26 CNS-negative patients who were frequency matched for risk factors associated with CNS involvement. Results were confirmed by real-time quantitative polymerase chain reaction analysis and validated using independent patient samples.
  
  
  RESULTS
  Interleukin-15 (IL-15) expression was consistently upregulated in leukemic cells of CNS-positive patients compared with CNS-negative patients. In multivariate analysis, IL-15 expression levels greater than the median were associated with CNS involvement compared with expression equal to or less than the median (odds ratio [OR] = 10.70; 95% CI, 2.95 to 38.81). Diagnostic likelihood ratios for CNS positivity were 0.09 (95% CI, 0.01 to 0.65) for the first and 6.93 (95% CI, 2.55 to 18.83) for the fourth IL-15 expression quartiles. In patients who were CNS negative at diagnosis, IL-15 levels greater than the median were associated with subsequent CNS relapse compared with expression equal to or less than the median (OR = 13.80; 95% CI, 3.38 to 56.31).
  
  
  CONCLUSIONS
  Quantification of leukemic IL-15 expression at diagnosis predicts CNS status and could be a new tool to further tailor CNS-directed therapy in childhood ALL.
authors.affiliation: Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.forename: Shai
authors.initials: S
authors.lastname: Izraeli
authors.forename: Anja
authors.initials: A
authors.lastname: Teichert
authors.forename: Peter
authors.initials: P
authors.lastname: Rhein
authors.forename: Julia
authors.initials: J
authors.lastname: Skokowa
authors.forename: Anja
authors.initials: A
authors.lastname: Möricke
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Andre
authors.initials: A
authors.lastname: Schrauder
authors.forename: Leonid
authors.initials: L
authors.lastname: Karawajew
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Ludwig
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.forename: Holger J
authors.initials: HJ
authors.lastname: Schünemann
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D019409:Interleukin-15 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018365:Neoplasm, Residual / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D019409:Interleukin-15; D012333:RNA, Messenger; D012334:RNA, Neoplasm